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14 pages, 965 KB

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Profiles of Growth Factors Secreted by In Vitro-Stimulated Paediatric Acute Leukaemia Blasts of Myeloid and Lymphoid Origin

by Anna Kozub, Rafał Szarek, Mikołaj Szczęsny, Dagmara Jaworska, Wojciech Młynarski, Jerzy Kowalczyk, Tomasz Szczepański, Zenon P. Czuba and Łukasz Sędek

Int. J. Mol. Sci. 2026, 27(2), 933; https://doi.org/10.3390/ijms27020933 (registering DOI) - 17 Jan 2026

Abstract

The research on cytokine or growth factor (GF) release by leukaemic blasts is a largely unexplored area. This study aimed to evaluate the differential secretory potential of paediatric B-cell precursor and T-cell acute lymphoblastic leukaemia (BCP-ALL and T-ALL, respectively) and acute myeloid leukaemia [...] Read more.

The research on cytokine or growth factor (GF) release by leukaemic blasts is a largely unexplored area. This study aimed to evaluate the differential secretory potential of paediatric B-cell precursor and T-cell acute lymphoblastic leukaemia (BCP-ALL and T-ALL, respectively) and acute myeloid leukaemia cells (AMLs) for selected GFs, both basally and upon stimulation with phytohemagglutinin (PHA), lipopolysaccharide (LPS), or phorbol 12-myristate 13-acetate with ionophore A23187 (PMA + I). The concentrations of five GFs: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) in the supernatants were measured using the Bio-Plex multiplex immunoassay. AML blasts showed the highest basal concentrations of G-CSF, GM-CSF, and VEGF. PHA and LPS stimulation non-selectively enhanced the secretion of G-CSF, GM-CSF, VEGF, and PDGF in BCP-ALL and AML blasts. PMA + I was the strongest GF release inducer, particularly for BCP-ALL and T-ALL blasts, with the latter also showing higher responsiveness to PHA and LPS. Our findings reveal differential, leukaemia-type dependent GF secretion patterns. Lineage-specific responses may be exploitable for targeted therapeutic approaches for distinct AL types. This study is the first to comprehensively assess the extracellular secretion of multiple GFs by paediatric AL cells in cultures using a Bio-Plex multiplex immunoassay. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 2350 KB

Open AccessArticle

Dasatinib and Quercetin Alleviate Retinal Ganglion Cell Dendritic Shrinkage and Promote Axonal Regeneration in Mice with Optic Nerve Injury

by Xin Bin, Shuyi Zhou, Yanxuan Xu, Si Chen, Shaowan Chen, Wen Yao, Yingjie Cao, Kunliang Qiu and Tsz Kin Ng

Int. J. Mol. Sci. 2025, 26(24), 12170; https://doi.org/10.3390/ijms262412170 - 18 Dec 2025

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Abstract

Optic nerve (ON) injury by trauma induces progressive retinal ganglion cell (RGC) death and axonal loss, which leads to irreversible visual impairment and even blindness. Recently, we discovered that cellular senescence is involved in RGC survival regulation post-ON injury, and senolytic (dasatinib and [...] Read more.

Optic nerve (ON) injury by trauma induces progressive retinal ganglion cell (RGC) death and axonal loss, which leads to irreversible visual impairment and even blindness. Recently, we discovered that cellular senescence is involved in RGC survival regulation post-ON injury, and senolytic (dasatinib and quercetin) treatments can promote RGC survival and electroretinography activity. Here, we aimed to further evaluate the effects of dasatinib and quercetin on RGC dendrites and axons in mice with an ON crush injury. Longitudinal in vivo imaging analysis demonstrated that the RGC dendritic shrinkage was significantly reduced in mice with both individual and combined treatment of dasatinib and quercetin as compared to the vehicle treatment group. Similarly, dasatinib and quercetin treatments significantly promoted axonal regeneration post-ON injury as compared to the vehicle-treated mice. RNA sequencing analysis showed that the differentially expressed genes were enriched in the response to glucocorticoid, calcium ion binding, and cerebral cortex development. Sybr green PCR and immunofluorescence analyses validated that the axonal extension-related gene, meteorin (Metrn), was significantly upregulated in the dasatinib-only and combined dasatinib and quercetin treatments. In summary, this study revealed that dasatinib and quercetin alleviated RGC dendritic shrinkage and promoted axonal regeneration in mice after ON injury, probably mediated through meteorin, suggesting the dendrite repair and axonal regeneration potentials of dasatinib and quercetin for traumatic optic neuropathy treatment. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 12136 KB

Open AccessArticle

BGN Secreted by Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression via Activation of TLR4-Mediated Erk and NF-κB Signaling Pathways

by Hiroki Yokoo, Yu-ichiro Koma, Naozane Nomura, Rikuya Torigoe, Masaki Omori, Takashi Nakanishi, Shoji Miyako, Takaaki Nakanishi, Takayuki Kodama, Manabu Shigeoka, Yoshihiro Kakeji and Masafumi Horie

Int. J. Mol. Sci. 2025, 26(24), 12024; https://doi.org/10.3390/ijms262412024 - 13 Dec 2025

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Abstract

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis due to aggressive invasion and therapy resistance. Cancer-associated fibroblasts (CAFs) are key stromal components that promote tumor progression; however, their specific roles in ESCC remain unclear. Using a direct co-culture model of ESCC [...] Read more.

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis due to aggressive invasion and therapy resistance. Cancer-associated fibroblasts (CAFs) are key stromal components that promote tumor progression; however, their specific roles in ESCC remain unclear. Using a direct co-culture model of ESCC cell lines (TE-9, -10, and -15) and mesenchymal stem cells (MSCs) to generate CAF-like cells, we identified biglycan (BGN) as a significantly upregulated gene in CAF-like cells via cDNA microarray analysis. Public single-cell RNA sequencing data also demonstrated elevated BGN expression in CAF clusters. We confirmed that CAF-like cells exhibited elevated BGN expression and secretion at both the mRNA and protein levels. Recombinant human BGN enhanced ESCC cell proliferation and migration by activating Erk and NF-κB signaling pathways, effects abrogated by TLR4 blockade. Furthermore, BGN promoted CAF marker expression in MSCs, M2-like macrophage polarization, and enhanced proliferation and migration abilities in both cell types. Immunohistochemical analysis of 66 ESCC tissues revealed that high stromal BGN expression correlated with greater tumor invasion, lymphatic invasion, and shorter disease-free survival. These findings indicate that CAF-derived BGN promotes ESCC progression via TLR4-mediated signaling and modulates stromal cell behavior, highlighting its potential as a prognostic biomarker and therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 977 KB

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Integrative sWGS: A New Paradigm for HRD Detection in Ovarian Cancer

by Dan Corneliu Jinga, Georgiana Duta-Cornescu, Danut Cimponeriu, Eirini Papadopoulou, Angeliki Meintani, George Tsaousis, Amalia Chirnogea, Irina Bucatariu, Polixenia-Georgeta Iorga, Diana Chetroiu, Sorin-Cornel Hosu, Amalia Hogea-Zah, Mircea-Dragos Median, Bogdan Diana, Dana-Lucia Stănculeanu, Raluca Mihaila, Dana-Sonia Nagy, Pompilia-Elena Motatu, Turcanu Eugeniu, Elena-Octaviana Cristea, Ion-Cristian Iaciu, Paul Kubelac and Andreea Truican Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(24), 11968; https://doi.org/10.3390/ijms262411968 - 12 Dec 2025

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Abstract

Homologous recombination deficiency (HRD) is a clinically relevant biomarker that predicts sensitivity to PARP inhibitors and enables personalized cancer therapy. Validated local HRD testing solutions are essential to ensure timely and equitable access, ultimately improving treatment outcomes. We evaluated a shallow whole-genome sequencing [...] Read more.

Homologous recombination deficiency (HRD) is a clinically relevant biomarker that predicts sensitivity to PARP inhibitors and enables personalized cancer therapy. Validated local HRD testing solutions are essential to ensure timely and equitable access, ultimately improving treatment outcomes. We evaluated a shallow whole-genome sequencing (sWGS) approach for genomic instability (GI) assessment combined with a 52-gene targeted panel in ovarian cancer. Validation used reference materials and 24 archival samples with prior HRD characterization, comparing performance with the Myriad myChoice^® HRD test. A prospective cohort of 124 newly diagnosed ovarian cancer patients was then analyzed. sWGS-derived GI status showed strong concordance with the reference test (95.8% overall agreement; κ = 0.913; NPV 100%, PPV 93.3%). Pathogenic BRCA1/2 variants were detected in 30 patients (24.19%). An additional 22.76% were BRCA1/2-negative but GI-positive, giving an overall HRD prevalence of 47.15%. Platinum sensitivity occurred in 90.0% (18/20) of HRD-positive patients with follow-up. Among 12 patients assessed for PARP-inhibitor response, the overall response rate was 66.7% (95% CI 39.1–86.2) and disease control rate 83.3% (95% CI 55.2–95.3). TP53 alterations were most frequent (62.90%), followed by BRCA1 (19.35%) and BRCA2 (4.83%). Pathogenic variants in other HR-pathway genes (ATM, CHEK2, BRIP1, RAD51C, BARD1) appeared in 9.57% of BRCA-wild-type cases, with heterogeneous GI impact. Two cases showed concurrent BRCA2 variants and microsatellite instability, indicating possible eligibility for anti-PD-1/PD-L1 therapy in addition to PARPi. This first comprehensive analysis of Romanian ovarian cancer patients suggests that integrating sWGS-based genomic instability assessment with BRCA testing can improve HRD detection and reflects the heterogeneity of HR-pathway variants. Preliminary clinical observations were consistent with known HRD-associated treatment responses, although larger studies are needed to confirm these findings. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 5556 KB

Open AccessArticle

Dictamnine Exhibits Anti-Asthmatic Effects by Modulating TGF-β/Smad2/3 Signaling in a Murine Asthma Model and Human Bronchial Epithelial Cells

by Myung-A Jung, Bu-Yeo Kim, Joo Young Lee, Kon-Young Ji, Mi Han Lee, Dong Ho Jung, Mudan Cai and Taesoo Kim

Int. J. Mol. Sci. 2025, 26(24), 11891; https://doi.org/10.3390/ijms262411891 - 10 Dec 2025

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Abstract

Current asthma therapies reduce inflammation and symptoms but there are concerns regarding adverse effects and the long-term treatment burden. The anti-asthmatic potential of Dictamnine (Dic) has not been investigated. The therapeutic effect of Dic on airway inflammation and remodeling was investigated by targeting [...] Read more.

Current asthma therapies reduce inflammation and symptoms but there are concerns regarding adverse effects and the long-term treatment burden. The anti-asthmatic potential of Dictamnine (Dic) has not been investigated. The therapeutic effect of Dic on airway inflammation and remodeling was investigated by targeting the tumor growth factor (TGF)-β/Smad2/3 pathway. A murine model of ovalbumin (OVA)-induced asthma was used to evaluate the effects of orally-administered Dic on airway hyperresponsiveness, inflammatory cytokines in bronchoalveolar lavage fluid (BALF), OVA-specific IgE in the serum, and histopathological changes. The expression of TGF-β/Smad2/3 and epithelial markers was assessed. Human bronchial epithelial cells were used in vitro to examine the effects of Dic on TGF-β-induced Smad2/3 phosphorylation. Network pharmacology was conducted to predict Dic-associated targets and pathways. Dic substantially reduced the levels of Th2 cytokines, mucin 5AC in BALF, and OVA-specific IgE in the serum. Histology indicated reduced inflammatory cell infiltration, bronchial wall thickening, and peribronchial fibrosis in Dic-treated mice. Dic downregulated TGF-β and p-Smad2/3 expression and upregulated ZO-1 expression in the lung tissue. Dic downregulated TGF-β-induced Smad2/3 phosphorylation in bronchial epithelial cells. Network pharmacology indicated enrichment of Dic-related genes in the TGF-β pathway. Dic exhibited anti-asthmatic effects and is a potential therapeutic candidate. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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19 pages, 1324 KB

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Effect of Central Injection of Anandamide on LPS-Dependent Suppression of GnRH/LH Secretion in Ewes During the Follicular Phase of the Estrous Cycle

by Karolina Wojtulewicz, Dorota Tomaszewska-Zaremba, Monika Tomczyk, Joanna Bochenek and Andrzej P. Herman

Int. J. Mol. Sci. 2025, 26(23), 11246; https://doi.org/10.3390/ijms262311246 - 21 Nov 2025

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Abstract

The study investigated the effects of intracerebroventricular (ICV) administration of the endocannabinoid anandamide (AEA) on suppression of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion during lipopolysaccharide (LPS)-induced inflammation in ewes at the follicular phase of the estrous cycle. Animals were divided into three groups: [...] Read more.

The study investigated the effects of intracerebroventricular (ICV) administration of the endocannabinoid anandamide (AEA) on suppression of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion during lipopolysaccharide (LPS)-induced inflammation in ewes at the follicular phase of the estrous cycle. Animals were divided into three groups: control, LPS (intravenous, IV; 400 ng/kg), and LPS + AEA (ICV; 100 µM/animal). In LPS-treated ewes, AEA increased GnRH concentration in the preoptic area (POA) and upregulated GnRH mRNA expression in the POA and anterior hypothalamus (AHA). Central administration of AEA decreased the circulating concentration of cortisol in LPS-treated ewes. Moreover, AEA lowered proinflammatory interleukin (IL)-1β and increased anti-inflammatory IL-10 protein expressions in the hypothalamus of LPS-treated ewes. However, ICV AEA did not reverse the inflammation-associated reduction in LH secretion. These findings show that acute central administration of AEA abolishes the inhibitory effect of inflammation on GnRH synthesis in the POA and even stimulates it, likely through attenuation of central inflammation, as reflected by IL-1β and IL-10 changes in the POA. Nevertheless, short-term AEA administration was insufficient to counteract the inflammation-mediated suppression of LH secretion. Further studies are needed to explore the role of endocannabinoids (ECBs) in modulating GnRH/LH secretion under inflammatory conditions, particularly with prolonged exposure. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 5677 KB

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Copy Number Alteration Profiling from Plasma cfDNA WES in Advanced NSCLC

by Ho Jang and Mi-Kyung Jeong

Int. J. Mol. Sci. 2025, 26(22), 11111; https://doi.org/10.3390/ijms262211111 - 17 Nov 2025

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Abstract

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read [...] Read more.

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read count patterns in cfDNA WES data, we developed and evaluated an advanced pipeline for robust CNA detection in patients with advanced non-small cell lung cancer (NSCLC). Read count signals showed strong correlation with GC content, and applying locally estimated scatterplot smoothing (LOESS)-based GC bias correction effectively reduced false positives and improved CNA detection. The resulting cfDNA CNA profiles were reproducible within patients and showed strong concordance with The Cancer Genome Atlas (TCGA) tissue-level patterns for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These findings demonstrate that cfDNA WES, when combined with appropriate bias correction, can serve as a practical and minimally invasive alternative for genomic characterization of NSCLC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 3932 KB

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Elevated Levels of Active GSK3β in the Blood of Patients with Myotonic Dystrophy Type 1 Correlate with Muscle Weakness

by Katherine Jennings, Cuixia Tian, Rebeccah L. Brown, Paul S. Horn, Benedikt Schoser, Hani Kushlaf, Nikolai A. Timchenko and Lubov Timchenko

Int. J. Mol. Sci. 2025, 26(21), 10760; https://doi.org/10.3390/ijms262110760 - 5 Nov 2025

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Abstract

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the [...] Read more.

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the small-molecule inhibitor of GSK3β, tideglusib (TG), reduces DM1 pathology in DM1 cell and mouse models by correcting the GSK3β-CUGBP1 pathway, decreasing the mutant CUG-containing RNA. Respectively, clinical trials using TG showed promising results for patients with congenital DM1 (CDM1). The drug development in DM1 human studies needs specific and noninvasive biomarkers. We examined the blood levels of active GSK3β in different clinical forms of DM1 and found an increase in active GSK3β in the peripheral blood mononuclear cells (PBMCs) in patients with CDM1, juvenile DM1 and adult-onset DM1 vs. unaffected patients. The blood levels of active GSK3β correlate with the length of CTG repeats and severity of muscle weakness. Thrombospondin and TGFβ, linked to the TG-GSK3β pathway in DM1, are also elevated in the DM1 patients’ blood. These findings show that the blood levels of active GSK3β might be developed as a potential noninvasive biomarker of muscle weakness in DM1. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 3604 KB

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HIF-2α Interaction with Ataxin-10 Enhances HIF-2α Binding to Its Target Gene Promoters

by Aikaterini Diseri, Ioanna-Maria Gkotinakou, Christina Befani, Ioannis Pappas, Martina Samiotaki, George Panayotou and Panagiotis Liakos

Int. J. Mol. Sci. 2025, 26(21), 10417; https://doi.org/10.3390/ijms262110417 - 27 Oct 2025

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Abstract

The master transcription factors that control cell adaptation under hypoxia are known as hypoxia-inducible factors or HIFs. HIF-2α is the second isoform, which has been studied less extensively, and its expression is limited to particular cell types and is associated with increased malignancy [...] Read more.

The master transcription factors that control cell adaptation under hypoxia are known as hypoxia-inducible factors or HIFs. HIF-2α is the second isoform, which has been studied less extensively, and its expression is limited to particular cell types and is associated with increased malignancy in tumors. Herein, we investigate the interaction of HIF-2α with Ataxin-10, an intracellular protein involved in cell survival and differentiation, as well as the mechanism and the effects of this interaction in cervical cancer (HeLa) and glioma (U-87MG) cells. The interaction was investigated by LC-MS/MS proteomic analysis, immunoprecipitation, and immunoblotting. HIF-2 transcriptional activity was measured by luciferase assays and quantitative RT-PCR of target genes specific to HIF-2. The mechanism of interaction was investigated using immunofluorescence microscopy analysis, subcellular fractionation, siRNA-mediated silencing, quantitative RT-PCR, in vitro binding assays, and chromatin immunoprecipitation (ChIP). Ataxin interacts specifically with HIF2α and binds to the HIF-2α carboxyterminal activation domain. The interaction of HIF-2α with Ataxin-10 increases HIF-2-transcriptional activity under hypoxia through the enhancement of HIF-2α binding to chromatin in Hypoxia Response Elements of HIF-2 specific target genes SERPINE1, CITED-2, and SOD-2. These new data highlight a novel HIF-2 fine-tuning mechanism and may offer new, effective therapeutic approaches for treating cancerous tumors. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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11 pages, 2079 KB

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Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence

by Dongguang Li, Athena Li, Ngoc DeSouza and Shaoguang Li

Int. J. Mol. Sci. 2025, 26(21), 10354; https://doi.org/10.3390/ijms262110354 - 24 Oct 2025

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Abstract

Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow [...] Read more.

Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow environment where both non-leukemic hematopoietic stem cells (HSCs) and LSCs reside. We believe the molecular and biological changes of these non-leukemic HSCs should be accompanied by the morphological changes of these cells. On the other hand, the quantity of these non-leukemic HSCs with morphological changes should reflect disease severity, prognosis and therapy responses. Thus, identification of non-leukemic HSCs in the leukemia bone marrow environment and monitoring of their quantity before, during and after treatments will potentially provide valuable information for correctly handling treatment plans and predicting outcomes. However, we have known that these morphological changes at the stem cell level cannot be extracted and identified by microscopic visualization with human eyes. In this study, we chose polycythemia vera (PV) as a disease model (a type of human myeloproliferative neoplasms derived from a hematopoietic stem cell harboring the JAK2V617F oncogene) to determine whether we can use artificial intelligence (AI) deep learning to identify and quantify non-leukemic HSCs obtained from bone marrow of JAK2V617F knock-in PV mice by analyzing single-cell images. We find that non-JAK2V617F-expressing HSCs are distinguishable from LSCs in the same bone marrow environment by AI with high accuracy (>96%). More importantly, we find that non-JAK2V617F-expressing HSCs from the leukemia bone marrow environment of PV mice are morphologically distinct from normal HSCs from a normal bone marrow environment of normal mice by AI with an accuracy of greater than 98%. These results help us prove the concept that non-leukemic HSCs undergo AI-recognizable morphological changes in the leukemia bone marrow environment and possess unique morphological features distinguishable from normal HSCs, providing a possibility to assess therapy responses and disease prognosis through identifying and quantitating these non-leukemic HSCs in patients. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 2616 KB

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GC Content and Thermal Stability of Double-Stranded RNA: Fragments of Microsporidia Vairimorpha ceranae and Nosema bombycis AT-Rich Genes Are Sensitive to Standard Heat Treatment

by Ruslan R. Fadeev, Sergey A. Timofeev, Igor V. Senderskiy and Viacheslav V. Dolgikh

Int. J. Mol. Sci. 2025, 26(21), 10270; https://doi.org/10.3390/ijms262110270 - 22 Oct 2025

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Abstract

Heating at 95 °C or boiling E. coli HT115 (DE3) cells is often used to extract heterologous dsRNA or kill bacteria, although these temperatures cause dsRNA denaturation and destruction. In this study, we examined the risk of degradation of dsRNA fragments of AT-rich [...] Read more.

Heating at 95 °C or boiling E. coli HT115 (DE3) cells is often used to extract heterologous dsRNA or kill bacteria, although these temperatures cause dsRNA denaturation and destruction. In this study, we examined the risk of degradation of dsRNA fragments of AT-rich genes at high temperature. The expression of dsRNA fragments of AT-rich genes encoding DNA replication enzymes from the microsporidia Vairimorpha ceranae and Nosema bombycis in E. coli HT115 (DE3) was accompanied by heating the bacteria at 95 °C for 30 min. In contrast to four control fragments with normal GC content, the AT-rich dsRNAs of microsporidia were destroyed by this treatment. The in vitro synthesis and heating of the studied dsRNAs showed the degradation of both microsporidia and control fragments. The thermal degradation of in vitro-synthesized control dsRNA with a normal GC content of 47.6% was prevented by the addition of 2 × YT media, NaCl, or low concentrations of MgSO₄. This demonstrates the important role of mono- and divalent cations in stabilizing heated fragments and helps explain the preservation of their integrity and RNAi-initiating activity despite the treatment of bacteria at temperatures that denature dsRNA. Feeding Colorado potato beetle larvae with the same in vitro-synthesized dsRNA containing fragments of three Leptinotarsa decemlineata genes showed that their thermal destruction was accompanied by a decrease in pest-suppressing activity. No dsRNA degradation was observed at 80 °C or after E. coli sonication, and these treatments, as well as increasing cation content, may help to avoid the degradation of heat-sensitive dsRNA. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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22 pages, 4166 KB

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Characterization of Recombinant Human Type II Collagen from CHO Cells, Functional Assessment of Chondrocytes and Alleviation of Cartilage Degeneration

by Chuan Wang, Zhijie Zhang, Zhengqi Zha, Chunyang Lu, Hang Wang, Long Yue and Hongping Yin

Int. J. Mol. Sci. 2025, 26(20), 10232; https://doi.org/10.3390/ijms262010232 - 21 Oct 2025

Cited by 1 | Viewed by 1303

Abstract

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 [...] Read more.

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 in biomedical fields. In this study, we achieved high-yield expression of full-length human Col2 (rhCol2) in CHO cells. The physical and chemical properties of rhCol2 were very close to native Col2, including molecular weight, triple helix structure, thermal stability and self-assembly capacity. Functional assays of primary chondrocytes have demonstrated that rhCol2 can effectively promote chondrocyte proliferation and increase the expression levels of cartilage-specific genes (Col2a1, Aggrecan, and Sox-9). Moreover, a cartilage defect model was surgically created in SD rats demonstrated that rhCol2 significantly enhanced cartilage repair, and the severity of the defect was assessed through histological and micro-CT analyses. Human chondrocytes were utilized to compare the effects of different collagens and verified through a series of functional experiments. In conclusion, these findings indicate that rhCol2 is an effective biomaterial and is expected to promote the application of recombinant collagen in the field of cartilage repair. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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20 pages, 1105 KB

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Does Genetic Variation in Detoxification Capacity Influence Hepatic Biomarker Responses to a Liver Support Supplementation Regimen?

by Markus Schauer, Susanne Mair, Michael Keiner, Christian Werner, Florian Kainz and Mohamad Motevalli

Int. J. Mol. Sci. 2025, 26(20), 10209; https://doi.org/10.3390/ijms262010209 - 20 Oct 2025

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Abstract

Genetic polymorphisms contribute to inter-individual variation in liver detoxification, influencing susceptibility to exposures and responses to interventions. While urinary biomarkers reflect Phase II activity, the impact of genotype on supplementation response remains unclear. In a pilot, prospective, open-label cohort study, 30 Austrian adults [...] Read more.

Genetic polymorphisms contribute to inter-individual variation in liver detoxification, influencing susceptibility to exposures and responses to interventions. While urinary biomarkers reflect Phase II activity, the impact of genotype on supplementation response remains unclear. In a pilot, prospective, open-label cohort study, 30 Austrian adults completed an 8-week multi-ingredient liver support supplementation regimen (e.g., glutathione, N-acetylcysteine, α-lipoic acid). First-morning urine was collected at baseline and follow-up for measurement of D-glucaric acid, mercapturic acids, and creatinine. Dried blood spots were genotyped for polymorphisms in detoxification genes (CYP1A1, GSTM1, GSTP1, GSTT1, and NQO1), and participants were stratified into normal (NDC) or limited (LDC) detoxification capacity groups. Adherence was monitored through logs, mid-study interviews, and product counts. The intervention led to modest reductions in body weight (−0.87 kg, p < 0.05) and BMI (−0.31 kg/m², p < 0.05), and significant increases in urinary D-glucaric acid (p < 0.05) and mercapturic acids (p < 0.01), with consistent responses across detoxification genotype groups (p > 0.05). The pattern of biomarker responses based on clinically defined categories did not differ significantly between the study groups (adjusted odds ratio = 2.88, p > 0.05). The observed increases in urinary biomarkers and reductions in weight and BMI are consistent with potential modulation of detoxification pathways following liver support supplementation, independent of genetic polymorphisms influencing detoxification capacity. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 334 KB

Open AccessArticle

The Prevalence of Second Neoplasms in Patients with Non-Aldosterone Producing Adrenocortical Lesions

by Paraskevi Tripolitsioti, Ariadni Spyroglou, Odysseas Violetis, Panagiota Konstantakou, Eleni Chouliara, Grigoria Betsi, Konstantinos Iliakopoulos, Eleni Memi, Konstantinos Bramis, Denise Kolomodi, Paraskevi Xekouki, Manousos Konstadoulakis, George Mastorakos and Krystallenia I Alexandraki

Int. J. Mol. Sci. 2025, 26(20), 10167; https://doi.org/10.3390/ijms262010167 - 19 Oct 2025

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Abstract

Over the last few decades, due to improvement in imaging techniques, the increased detection of adrenal incidentalomas is observed. Non-aldosterone producing adrenal adenomas (NAPACAs) often co-exist with second benign or malignant lesions. In the present study, we aimed to assess the presence of [...] Read more.

Over the last few decades, due to improvement in imaging techniques, the increased detection of adrenal incidentalomas is observed. Non-aldosterone producing adrenal adenomas (NAPACAs) often co-exist with second benign or malignant lesions. In the present study, we aimed to assess the presence of second neoplasms, both benign and malignant, in patients with NAPACAs, and to investigate possible correlations with clinical parameters, hormonal characteristics and the emergence of comorbidities. A total of 130 NAPACA patients were included in this single-center retrospective study. In this cohort, 35.4% of NAPACA patients carried any second neoplasm (either benign or malignant) whereas, 26.9% had a second malignant neoplasm. Cortisol levels after 1 mg overnight dexamethasone suppression test (F-ODS) were significantly higher in patients without a second neoplasm (p = 0.02), and this finding was consistent even when categorizing patients with and without malignancies (p = 0.02). In line with this observation, ACTH/F-ODS levels were significantly higher in patients with second malignancies (p < 0.05). Interestingly, the presence of mild autonomous cortisol secretion tended to be lower in patients with second malignancies (p = 0.08). No remarkable differences in the comorbidities of NAPACA patients with and without a second neoplasm were documented. Further prospective studies will be needed to elucidate the role of mild hypercortisolemia on the development of these second tumors in NAPACA patients. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1827 KB

Open AccessArticle

Utility of Serum HBV RNA Measurement During Nucleoside/Nucleotide Analog Therapy in Chronic Hepatitis B Patients

by Keiichi Hiraoka, Masataka Tsuge, Michihiko Kawahara, Hatsue Fujino, Yasutoshi Fujii, Atsushi Ono, Eisuke Murakami, Tomokazu Kawaoka, Daiki Miki, C. Nelson Hayes, Seiya Kashiyama, Sho Mokuda, Shinichi Yamazaki and Shiro Oka

Int. J. Mol. Sci. 2025, 26(20), 10141; https://doi.org/10.3390/ijms262010141 - 18 Oct 2025

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Abstract

Hepatitis B virus (HBV) particles containing HBV RNA are secreted into the blood; these RNA-containing particles are non-infectious byproducts of the replication cycle and are distinct from mature, DNA-containing virions. The proportion of these particles increases during nucleoside/nucleotide analog therapy, but the clinical [...] Read more.

Hepatitis B virus (HBV) particles containing HBV RNA are secreted into the blood; these RNA-containing particles are non-infectious byproducts of the replication cycle and are distinct from mature, DNA-containing virions. The proportion of these particles increases during nucleoside/nucleotide analog therapy, but the clinical significance of serum HBV RNA remains unclear. We evaluated longitudinal changes in serum HBV RNA and their association with the antiviral efficacy of nucleoside/nucleotide analog therapy. Eighty-six patients with chronic HBV infection (baseline HBV DNA ≥ 5.0 Log IU/mL and ALT < 500 U/L) treated with entecavir (ETV, N = 80) or tenofovir alafenamide (TAF, N = 6) were included. Serum HBV RNA was quantified using Cobas HBV RNA (RUO) at baseline, week 12, and week 48. Associations with clinical variables and treatment response were analyzed. Baseline HBV RNA correlated with HBsAg, HBV DNA, and hepatitis B core-related antigen. Both HBV DNA and RNA tended to decrease with advanced liver fibrosis. HBV DNA and RNA declines did not differ between HBeAg-positive and -negative patients, but the HBV RNA/DNA ratio at week 48 was significantly higher in HBeAg-positive cases (p < 0.001). Patients with baseline ALT ≥ 100 U/L showed significantly lower RNA levels at weeks 12 and 48 (p = 0.004, p < 0.001). While HBV DNA decline was similar between ETV and TAF (p = 0.076), RNA decline was significantly greater with TAF at week 12 (p = 0.027). Serum HBV RNA reflects intrahepatic viral replication and may not be influenced by fibrosis progression. HBV RNA decline during nucleoside/nucleotide analog therapy differed between ETV and TAF, suggesting drug-specific effects on viral RNA dynamics. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 9834 KB

Open AccessArticle

Cardiac Troponin I Antibodies Induce Cardiomyocyte Damage and Alter Cell Morphology

by Jennifer Furkel, Vanessa A. Zirkenbach, Maximilian Knoll, Renate Öttl, Katrin Rein, Amir Abdollahi, Norbert Frey, Mathias H. Konstandin and Ziya Kaya

Int. J. Mol. Sci. 2025, 26(20), 10005; https://doi.org/10.3390/ijms262010005 - 14 Oct 2025

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Abstract

Circulating heart-reactive autoantibodies (aAbs) detected in a variety of heart diseases (e.g., myocarditis, dilated cardiomyopathy, and myocardial infarction) have been associated with the progression of heart failure and a poor prognosis. However, the underlying mechanisms remain largely unknown. We investigated the effects of [...] Read more.

Circulating heart-reactive autoantibodies (aAbs) detected in a variety of heart diseases (e.g., myocarditis, dilated cardiomyopathy, and myocardial infarction) have been associated with the progression of heart failure and a poor prognosis. However, the underlying mechanisms remain largely unknown. We investigated the effects of murine plasma containing aAbs against cardiac troponin I (cTnI) on neonatal rat cardiomyocytes (NRCMs). An autoimmune response to cTnI in A/J mice was induced, and anti-cTnI-aAbs were quantified. After 21 days, cardiac function, inflammation, fibrosis, and apoptosis were evaluated. In complementary in vitro liquid biopsy experiments, NRCMs were incubated with murine plasma containing high anti-cTnI-aAb levels or corresponding controls. Morphological phenotyping was performed using the C-MORE fluorescent image-based analysis workflow. Immunization with cTnI resulted in high anti-cTnI-aAb production, followed by myocardial inflammation, fibrosis, and impaired ejection fraction. NRCMs exposed to anti-cTnI-aAb-containing plasma showed reduced cell size, altered shape and radius, and elevated rate of dead cells in cell cycle analysis (p < 0.01, for 20% plasma). Together, these findings suggest a direct interaction of anti-cTnI-aAbs on cardiomyocytes, likely promoting adverse myocardial remodeling in vivo. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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29 pages, 4696 KB

Open AccessArticle

Exploring the Role of Heat Shock Proteins in Neuroimmune Modulation in Rheumatoid Arthritis: Insights from a Rat Model

by Malak Fouani, Federica Scalia, Giuseppe Donato Mangano, Francesca Rappa, Wassim Abou-Kheir, Angelo Leone, Nada Lawand and Rosario Barone

Int. J. Mol. Sci. 2025, 26(19), 9743; https://doi.org/10.3390/ijms26199743 - 7 Oct 2025

Viewed by 920

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments [...] Read more.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments are not curative for RA. Heat Shock Proteins (HSPs) are molecular chaperones with immunoregulatory properties; however, their role is not yet fully understood, as these molecules may play a dual, pro- and anti-inflammatory role. In this study, we evaluated the protein expression levels of HSPs 27, 60, 70, and 90 in the synovial membrane and spinal cord of the RA rats’ model to determine their roles during the disease course, both on the neurological and immunological levels. Furthermore, HSP levels have been evaluated in the spinal cord of control and RA rats’ model after high and low doses of ketamine injection. Significant changes in Hsp60, 70, and 90 expression levels were observed only in the spinal cord of RA rats. We demonstrated that blocking N-methyl-D-aspartate receptors with ketamine can modulate spinal cord HSPs expression in RA rats and subsequently impact neurogenic inflammation and adult neurogenesis. This suggests that HSPs may be a promising target for RA treatment due to their complex immunomodulatory effects and potential interactions with the nervous system. Further research is needed to explore their therapeutic potential and develop effective interventions for RA. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 3367 KB

Open AccessArticle

Effect of Chronic Social Defeat Stress on the Small-Intestinal Environment, Including the Gut Flora, Immune System, and Mucosal Barrier Integrity

by Soichi Yagi, Hirokazu Fukui, Tetsuya Shiraishi, Koji Kaku, Midori Wakita, Yasuhiro Takagi, Maiko Ikenouchi, Toshiyuki Sato, Mikio Kawai, Yoko Yokoyama, Tetsuya Takagawa, Toshihiko Tomita, Shiho Kitaoka and Shinichiro Shinzaki

Int. J. Mol. Sci. 2025, 26(19), 9359; https://doi.org/10.3390/ijms26199359 - 25 Sep 2025

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Abstract

Psychological stress is deeply involved in the pathophysiology of gastrointestinal diseases. We investigated the effect of psychological stress on the small-intestinal environment, including gut flora, immune system, and mucosal integrity in mice subjected to chronic social defeat stress (CSDS). CSDS mice were established [...] Read more.

Psychological stress is deeply involved in the pathophysiology of gastrointestinal diseases. We investigated the effect of psychological stress on the small-intestinal environment, including gut flora, immune system, and mucosal integrity in mice subjected to chronic social defeat stress (CSDS). CSDS mice were established by exposing a C57BL/6N mouse to an ICR aggressor mouse. Stool samples were obtained to investigate its properties and the gut microbiome profile. Using small-intestinal tissues, the expression of cytokines, antimicrobial peptides, and tight junction proteins (TJPs) were examined by real-time RT-PCR and immunohistochemistry. Small-intestinal permeability was evaluated by transepithelial electrical resistance assay. For stool properties, mean Bristol scale score and fecal water content were significantly lower in the CSDS group. Pseudomonadota and Patescibacteria were significantly more abundant in the stools from CSDS mice. Among TJPs and antimicrobial peptides, the expression of Occludin, Claudin-4, and Regenerating gene IIIγ was significantly decreased in the small intestine epithelium of CSDS mice. The small-intestinal permeability was significantly increased in CSDS mice. Lipopolysaccharide immunoreactivity, the number of macrophages, and proinflammatory IL-1β expression were significantly increased in the small intestine of CSDS mice. These findings suggest that psychological stress is associated with mucosal barrier dysfunction and microinflammation in small-intestinal tissues. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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20 pages, 6242 KB

Open AccessArticle

Non-Canonical Compartmentalization of DROSHA Protein at the Golgi Apparatus: miRNA Biogenesis-Independent Functionality in Human Cancer Cells of Diverse Tissue Origin

by Eleni I. Theotoki, Panos Kakoulidis, Kostas A. Papavassiliou, Konstantinos-Stylianos Nikolakopoulos, Eleni N. Vlachou, Efthimia K. Basdra, Athanasios G. Papavassiliou, Ourania E. Tsitsilonis, Gerassimos E. Voutsinas, Athanassios D. Velentzas, Ema Anastasiadou and Dimitrios J. Stravopodis

Int. J. Mol. Sci. 2025, 26(19), 9319; https://doi.org/10.3390/ijms26199319 - 24 Sep 2025

Cited by 1 | Viewed by 3280

Abstract

DROSHA protein is widely known for its essential role in the microRNA (miRNA/miR) biogenesis pathway where, together with its co-factor DGCR8, it forms the “Microprocessor” complex and catalyzes the primary miRNA (pri-miRNA) processing in the nucleus. Nevertheless, DROSHA also seems to participate in [...] Read more.

DROSHA protein is widely known for its essential role in the microRNA (miRNA/miR) biogenesis pathway where, together with its co-factor DGCR8, it forms the “Microprocessor” complex and catalyzes the primary miRNA (pri-miRNA) processing in the nucleus. Nevertheless, DROSHA also seems to participate in several miRNA-independent cellular mechanisms, such as transcriptional regulation, RNA processing and genome integrity maintenance. Hence, the present study aims to further investigate novel miRNA-independent activities of DROSHA protein, with potentially regulatory roles in the oncogenesis of human cancer cells. Our results reveal a new, strong profile of microprocessor-independent DROSHA localization at the Golgi apparatus in several human cancer cell lines of different tissue origin, with hepatic carcinoma, thyroid cancer, urothelial bladder cancer, colon carcinoma and melanoma being the cellular model systems herein examined. Notably, oncogenic activity, malignancy grade and metastatic capacity are shown to be strongly associated with DROSHA’s compartmentalization at Golgi, a phenotype that does not seem to rely on p53 protein’s functionality. Taken together, through employment of advanced confocal laser scanning microscopy (CLSM) and molecular modeling, we herein unveil the ability of DROSHA, but not AGO2 and DICER, to reside at Golgi, where DROSHA can physically interact with the GM130 Golgi-specific component, thus indicating DROSHA’s engagement in non-canonical and miRNA-independent—but also Golgi apparatus-dependent—novel mechanisms that can be tightly coupled with malignancy dynamics and beneficially utilized as potential biomarkers and therapeutic targets for human cancer. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 6419 KB

Open AccessArticle

Lactiplantibacillus plantarum HY7715 Alleviates Restraint Stress-Induced Anxiety-like Behaviors by Modulating Oxidative Stress, Apoptosis, and Mitochondrial Function

by Kippuem Lee, Daehyeop Lee, Haeryn Jeong, Joo Yun Kim, Jae Jung Shim and Jae Hwan Lee

Int. J. Mol. Sci. 2025, 26(18), 9251; https://doi.org/10.3390/ijms26189251 - 22 Sep 2025

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Abstract

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast [...] Read more.

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 10⁹ CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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40 pages, 3769 KB

Open AccessArticle

Deciphering European Sea Bass (Dicentrarchus labrax) Resistance to Nervous Necrosis Virus by Transcriptome Analysis from Early Infection Towards Establishment of Virus Carrier State

by Dimitra K. Toubanaki, Odysseas-Panagiotis Tzortzatos, Antonia Efstathiou, Vasileios Bakopoulos and Evdokia Karagouni

Int. J. Mol. Sci. 2025, 26(18), 9220; https://doi.org/10.3390/ijms26189220 - 21 Sep 2025

Viewed by 1225

Abstract

Viral nervous necrosis, caused by the nervous necrosis virus (NNV), is an important threat to aquaculture, causing great economic losses and a high environmental burden. European sea bass (Dicentrarchus labrax) is highly affected by NNV, and selective breeding programs for disease [...] Read more.

Viral nervous necrosis, caused by the nervous necrosis virus (NNV), is an important threat to aquaculture, causing great economic losses and a high environmental burden. European sea bass (Dicentrarchus labrax) is highly affected by NNV, and selective breeding programs for disease resistance have been established in order to achieve a sustainable aquaculture and minimize the need for vaccines, drugs and antibiotics. Resistant and susceptible European sea bass were experimentally challenged with NNV and their head kidney transcriptomes were analyzed at three time points, i.e., 3 hpi, 2 dpi and 14 dpi. Numerous differentially expressed genes (DEGs) were identified in the head kidneys of resistant and susceptible infected vs. non-infected sea bass. Gene ontology enrichment, pathway, and protein–protein interaction analyses revealed that the NNV-resistant fish control their response to viral infection more efficiently, utilizing different mechanisms compared to the susceptible fish. Resistant fish displayed higher levels of interferon-related elements, cytokines, antigen presentation, T-cell activity, apoptosis, and programmed cell death combined with a controlled inflammatory response and more active proteasome and lysosome functions. The susceptible fish appeared to have high immune responses at the early infection stages, accompanied by high expressions of inflammatory, complement and coagulation pathways. Insulin metabolism was better regulated in the resistant fish and the control of lipid metabolism was less effective in the susceptible family. The cytoskeleton- and cell adhesion-related pathways were mostly down-regulated in the susceptible fish, and the intracellular transport and motor proteins were utilized more efficiently by the resistant fish. The present study represents a thorough transcriptomic analysis of NNV infection effects on a resistant and a susceptible European sea bass head kidney. The obtained results provide valuable information on the mechanisms that offers pathogen resistance to a host, with many aspects that can be exploited to develop more efficient approaches to fighting viral diseases in aquaculture. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1626 KB

Open AccessArticle

Temporal and Spatial Dynamics in the Regulation of Myocardial Metabolism During the Ischemia-Reperfusion Process

by Elena de Dios, Maria J. Forteza, Nerea Perez-Sole, Tamara Molina-Garcia, Jose Gavara, Victor Marcos-Garces, Manuel Jimenez-Navarro, Amparo Ruiz-Sauri, Cesar Rios-Navarro and Vicente Bodi

Int. J. Mol. Sci. 2025, 26(18), 8820; https://doi.org/10.3390/ijms26188820 - 10 Sep 2025

Cited by 1 | Viewed by 951

Abstract

Although cardiac metabolic adaptation has been observed in response to the ischemia–reperfusion, the specific temporal and spatial changes occurring in the main regulators of myocardial glucolipid metabolism in the infarcted heart have not been fully characterized. Myocardial infarction (MI) was induced in female [...] Read more.

Although cardiac metabolic adaptation has been observed in response to the ischemia–reperfusion, the specific temporal and spatial changes occurring in the main regulators of myocardial glucolipid metabolism in the infarcted heart have not been fully characterized. Myocardial infarction (MI) was induced in female swine by transient coronary occlusion. The study design consisted of one control and four MI groups (no reperfusion, 1 min, 1 week, and 1 month after reperfusion). Metabolites obtained from the coronary sinus were determined at baseline, during ischemia, and after coronary reperfusion. mRNA expression of genes related to beta-oxidation and glucose transport were quantified in the five experimental groups and in three myocardial regions (infarcted, adjacent, and remote). In the coronary sinus, reduced glucose and increased lactate levels were detected during ischemia and soon after reperfusion. However, non-esterified fatty acids increased during reperfusion. A general upregulation of genes implicated in glycolysis and beta-oxidation occurred during ischemia and few minutes after reperfusion. Contrarily, heightened mRNA expression of glucose transporters and decay in regulators of beta-oxidation were observed one week after coronary reperfusion. Glycolysis and beta-oxidation are activated during ischemia and few minutes after coronary reopening, while a shift from beta-oxidation to glycolysis is evidenced a few days afterwards. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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27 pages, 3474 KB

Open AccessArticle

A ‘Spicy’ Mechanotransduction Switch: Capsaicin-Activated TRPV1 Receptor Modulates Osteosarcoma Cell Behavior and Drug Sensitivity

by Arianna Buglione, David Becerril Rodriguez, Simone Dogali, Giulia Alloisio, Chiara Ciaccio, Marco Luce, Stefano Marini, Luisa Campagnolo, Antonio Cricenti and Magda Gioia

Int. J. Mol. Sci. 2025, 26(18), 8816; https://doi.org/10.3390/ijms26188816 - 10 Sep 2025

Cited by 1 | Viewed by 1410

Abstract

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify [...] Read more.

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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21 pages, 2258 KB

Open AccessArticle

Neurotransmitter Genes in the Nucleus Accumbens That Are Involved in the Development of a Behavioral Pathology After Positive Fighting Experiences and Their Deprivation: A Conceptual Paradigm for Data Analysis

by Natalia N. Kudryavtseva, Dmitry A. Smagin, Olga E. Redina, Irina L. Kovalenko, Anna G. Galyamina and Vladimir N. Babenko

Int. J. Mol. Sci. 2025, 26(17), 8580; https://doi.org/10.3390/ijms26178580 - 3 Sep 2025

Cited by 1 | Viewed by 1175

Abstract

It has been shown previously that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior, with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main [...] Read more.

It has been shown previously that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior, with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main neurotransmitter events in some brain regions of aggressive male mice. Fighting deprivation (a no-fight period of 2 weeks) causes a significant increase in their aggressiveness. This paper is aimed at studying—after a period of fighting deprivation—the involvement of genes (associated with neurotransmitter systems within the nucleus accumbens) in the above phenomena. The nucleus accumbens is known to participate in reward-related mechanisms of aggression. We found the following differentially expressed genes (DEGs), whose expression significantly differed from that in controls and/or mice with positive fighting experience in daily agonistic interactions followed by fighting deprivation: catecholaminergic genes Th, Drd1, Drd2, Adra2c, Ppp1r1b, and Maoa; serotonergic genes Maoa, Htr1a, Htr1f, and Htr3a; opioidergic genes Oprk1, Pdyn, and Penk; and glutamatergic genes Grid1, Grik4, Grik5, Grin3a, Grm2, Grm5, Grm7, and Gad1. The expression of DEGs encoding proteins of the GABAergic system in experienced aggressive male mice mostly returned to control levels after fighting deprivation, except for Gabra5. In light of the conceptual paradigm for analyzing data that was chosen in our study, the aforementioned DEGs associated with the behavioral pathology can be considered responsible for consequences of aggression followed by fighting deprivation, including mechanisms of an aggression relapse. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 802 KB

Open AccessArticle

Salivary Protein Profile in Patients with Recurrent Aphthous Stomatitis: A Pilot Proteomic Study

by Francesco Franco, Nima Namarvari, Alessio Gambino, Federica Romano, Barbara Pergolizzi, Jianjian Zhang, Giuliana Abbadessa, Barbara Mognetti, Adriano Ceccarelli, Paolo Giacomo Arduino and Giovanni Nicolao Berta

Int. J. Mol. Sci. 2025, 26(16), 7878; https://doi.org/10.3390/ijms26167878 - 15 Aug 2025

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Abstract

Recurrent aphthous stomatitis (RAS) is the most common ulcerative disorder of the oral cavity, although its etiology is still unknown. The present study aimed to identify the proteomic profile associated with the RAS inflammatory process, thereby enhancing our understanding of its etiopathogenesis. We [...] Read more.

Recurrent aphthous stomatitis (RAS) is the most common ulcerative disorder of the oral cavity, although its etiology is still unknown. The present study aimed to identify the proteomic profile associated with the RAS inflammatory process, thereby enhancing our understanding of its etiopathogenesis. We compared salivary protein profiles of RAS patients during an active episode of oral ulceration (30 patients, mean age 36.9) to those from healthy donors without a history of RAS (30 healthy subjects, mean age 37.9). Using 2D-electrophoresis and mass spectrometry (MALDI-TOF) analysis, we identified 17 proteins that were differentially expressed in the two groups. Notably, Cystatin SN (CST1) appeared to be significantly downregulated in RAS patients. These findings were validated by Western blot analysis: CST1 was detected in only 3 of the 30 RAS cases, while it was strongly expressed in all the healthy subjects. Although preliminary, our results suggest a potential role for CST1 in the etiopathogenesis of RAS. Interestingly, the relative absence of CST1 in RAS patients seems to align with some clinical and molecular features of this disease. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessReview

Biomolecular Condensates in Disease: Decoding the Material State and Engineering Precision Modulators

by Biwei Han, Boxian Li, Xingyue Wang and Liang Wang

Int. J. Mol. Sci. 2026, 27(2), 837; https://doi.org/10.3390/ijms27020837 - 14 Jan 2026

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Abstract

The recognition of liquid–liquid phase separation (LLPS) as a widespread organizing principle has revolutionized our view of cellular biochemistry. By forming biomolecular condensates, cells spatially orchestrate reactions without membranes. However, the dysregulation of this precise physical organization is emerging as a driver of [...] Read more.

The recognition of liquid–liquid phase separation (LLPS) as a widespread organizing principle has revolutionized our view of cellular biochemistry. By forming biomolecular condensates, cells spatially orchestrate reactions without membranes. However, the dysregulation of this precise physical organization is emerging as a driver of diverse pathologies, collectively termed “Condensatopathies.” Unlike traditional proteinopathies defined by static aggregates, these disorders span a dynamic spectrum of material state dysfunctions, from the failure to assemble essential compartments to the formation of aberrant, toxic phases. While research has largely focused on neurodegeneration and cancer, the impact of condensate dysfunction likely extends across broad physiological landscapes. A central unresolved challenge lies in deciphering the “molecular grammar” that governs the transition from functional fluids to pathological solids and, critically, visualizing these transitions in situ. This “material science” perspective presents a profound conundrum for drug discovery: how to target the collective physical state of a protein ensemble rather than a fixed active site. This review navigates the evolving therapeutic horizon, examining the limitations of current pharmacological approaches in addressing the complex “condensatome.” Moving beyond inhibition, we propose that the future of intervention lies in “reverse-engineering” the biophysical codes of phase separation. We discuss how deciphering these principles enables the creation of programmable molecular tools—such as synthetic peptides and state-specific degraders—designed to precisely modulate or dismantle pathological condensates, paving the way for a new era of precision medicine governed by soft matter physics. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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32 pages, 1325 KB

Open AccessReview

AI-Based Prediction of Gene Expression in Single-Cell and Multiscale Genomics and Transcriptomics

by Ema Andreea Pălăștea, Irina-Mihaela Matache, Eugen Radu, Octavian Henegariu and Octavian Bucur

Int. J. Mol. Sci. 2026, 27(2), 801; https://doi.org/10.3390/ijms27020801 - 13 Jan 2026

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Abstract

Omics research is changing the way medicine develops new strategies for diagnosis, prevention, and treatment. With the surge of advanced machine learning models tailored for omicss analysis, recent research has shown improved results and pushed the progress towards personalized medicine. The dissection of [...] Read more.

Omics research is changing the way medicine develops new strategies for diagnosis, prevention, and treatment. With the surge of advanced machine learning models tailored for omicss analysis, recent research has shown improved results and pushed the progress towards personalized medicine. The dissection of multiple layers of genetic information has provided new insights into precision medicine, at the same time raising issues related to data abundance. Studies focusing on single-cell scale have upgraded the knowledge about gene expression, revealing the heterogeneity that governs the functioning of multicellular organisms. The amount of information gathered through such sequencing techniques often exceeds the human capacity for analysis. Understanding the underlying network of gene expression regulation requires advanced computational tools that can deal with the complex analytical data provided. The recent emergence of artificial intelligence-based frameworks, together with advances in quantum algorithms, has the potential to enhance multiomicsc analyses, increasing the efficiency and reliability of the gene expression profile prediction. The development of more accurate computational models will significantly reduce the error rates in interpreting large datasets. By making analytical workflows faster and more precise, these innovations make it easier to integrate and interrogate multi-omics data at scale. Deep learning (DL) networks perform well in terms of recognizing complex patterns and modeling non-linear relationships that enable the inference of gene expression profiles. Applications range from direct prediction of DNA sequence-informed predictive modeling to transcriptomic and epigenetic analysis. Quantum computing, particularly through quantum machine learning methods, is being explored as a complementary approach for predictive modeling, with potential applications to complex gene interactions in increasingly large and high-dimensional biological datasets. Together, these tools are reshaping the study of complex biological data, while ongoing innovation in this field is driving progress towards personalized medicine. Overall, the combination of high-resolution omics and advanced computational tools marks an important shift toward more precise and data-driven clinical decision-making. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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42 pages, 6458 KB

Open AccessReview

Clonal Hematopoiesis of Indeterminate Potential and Cardiometabolic Disease: Challenges, Controversies and Future Perspectives

by Ioanna A. Anastasiou, Dimitris Kounatidis, Natalia G. Vallianou, Eleni Rebelos, Irene Karampela and Maria Dalamaga

Int. J. Mol. Sci. 2026, 27(1), 233; https://doi.org/10.3390/ijms27010233 - 25 Dec 2025

Viewed by 723

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of hematopoietic stem cells harboring leukemogenic mutations in the absence of overt malignancy. Strongly associated with advancing age, CHIP is detected by next-generation sequencing of peripheral blood in more than 20% of [...] Read more.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of hematopoietic stem cells harboring leukemogenic mutations in the absence of overt malignancy. Strongly associated with advancing age, CHIP is detected by next-generation sequencing of peripheral blood in more than 20% of individuals over 80, most commonly through mutations in DNMT3A, TET2, ASXL1, and PPM1D. While CHIP confers over a four-fold increased risk of hematologic malignancy, it has recently emerged as a key determinant of cardiometabolic health. Epidemiological data indicated a 40% higher cardiovascular disease (CVD) risk events and a 34% increase in all-cause mortality among CHIP carriers, with specific mutations and larger clone sizes conferring greater cardiovascular burden. Preclinical studies have shown that macrophages deficient in TET2 or DNMT3A drive interleukin (IL)-1β/IL-6 inflammasome activation, thereby promoting atherosclerosis and metabolic dysfunction, whereas the JAK2V617F mutation accelerates thrombosis. CHIP integrates into a broader network of dysregulation encompassing adiposity and inflammaging, which underlies its association with diverse comorbidities, including type 2 diabetes (T2D), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). Multi-omics approaches have identified epigenetic and proteomic signatures correlated with CHIP expansion, providing potential biomarkers for risk stratification. Despite growing evidence of its systemic impact, CHIP screening remains limited to research settings. Emerging therapeutic strategies, including inflammasome inhibition, STING modulation, and epigenetic restoration, highlight its potential as a modifiable risk factor. This narrative review synthesizes current epidemiological, mechanistic, and translational insights, framing CHIP as an emerging causal factor in cardiometabolic disease and as a promising target for precision medicine in aging populations. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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23 pages, 1644 KB

Open AccessReview

The CTDP1 Founder Variant in CCFDN: Insights into Pathogenesis, Phenotypic Spectrum and Therapeutic Approaches

by Iulia Maria Sabau, Alexandra Chera, Victor Gabriel Ungureanu, Mircea Cretu Stancu, Adela Chirita-Emandi, Matthew Wood, Maria Puiu and Octavian Bucur

Int. J. Mol. Sci. 2026, 27(1), 34; https://doi.org/10.3390/ijms27010034 - 19 Dec 2025

Viewed by 408

Abstract

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 [...] Read more.

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1’s broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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48 pages, 1364 KB

Open AccessReview

Restoring Sight: The Journey of AIPL1 from Discovery to Therapy

by Alima Galieva, Alexander Karabelsky and Alexander D. Egorov

Int. J. Mol. Sci. 2025, 26(24), 12066; https://doi.org/10.3390/ijms262412066 - 15 Dec 2025

Viewed by 436

Abstract

Leber congenital amaurosis (LCA) is a severe inherited retinal disorder manifesting at birth or in early infancy, with a subset of cases linked to mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene. Initially identified as the disease locus for [...] Read more.

Leber congenital amaurosis (LCA) is a severe inherited retinal disorder manifesting at birth or in early infancy, with a subset of cases linked to mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene. Initially identified as the disease locus for LCA4, AIPL1 exhibits a retina-specific expression pattern. Its protein product is a unique member of the FKBP family, distinguished by its specific structural features and specialized functions. A wide spectrum of mutations in AIPL1 is associated with varying severities of retinal degeneration, implicating diverse pathogenic mechanisms. While the early onset and rapid progression of AIPL1-related disorders pose a therapeutic challenge, significant progress in gene therapy has unlocked promising avenues for effective treatment. This comprehensive review summarizes current findings to spark interest and pave the way for further studies in the therapy of AIPL1-caused retinal diseases. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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35 pages, 503 KB

Open AccessReview

Oxidative Stress, Antioxidant Cofactor Micronutrients, and Cognitive Outcomes in Childhood Obesity: Mechanisms, Evidence, and Therapeutic Opportunities

by Marina Darenskaya, Karen J. Cloete, Luybov Rychkova, Sergey Kolesnikov, Zhanna Prokhorova, Natalya Semenova, Natalya Yuzvak and Lyubov Kolesnikova

Int. J. Mol. Sci. 2025, 26(24), 12012; https://doi.org/10.3390/ijms262412012 - 13 Dec 2025

Viewed by 790

Abstract

Overweight and obesity are major public health concerns among children and adolescents worldwide. The most prevalent form is exogenous–constitutional obesity, which is driven by a sedentary lifestyle and an unhealthy diet in which caloric intake exceeds energy expenditure. Beyond their association with chronic [...] Read more.

Overweight and obesity are major public health concerns among children and adolescents worldwide. The most prevalent form is exogenous–constitutional obesity, which is driven by a sedentary lifestyle and an unhealthy diet in which caloric intake exceeds energy expenditure. Beyond their association with chronic disease, these factors are closely linked to deficits in cognitive development and executive functions essential for learning (including working memory, sustained attention, planning, behavioral self-regulation, and cognitive flexibility). Oxidative stress (OS), characterized by the accumulation of reactive oxygen species (ROS) in cells and extracellular fluids, is a significant potential mediator in childhood obesity and an important contributor to its comorbidities. The antioxidant defense system (AOD)’s activity largely depends on levels of trace element cofactors, which determine the body’s resistance to adverse environmental factors (the “maladaptation phenomenon”). OS and trace element deficiencies contribute to the development of morphological changes in the brain, thus serving as a critical connecting link between childhood obesity and cognitive impairment. Non-pharmacological interventions are the most accessible and effective approach for prevention and treatment. Bioactive compounds derived from food and natural plants, classified as antioxidants and phytopreparations, may represent a promising complementary approach. These compounds are most effective when used in combination with sustained lifestyle modifications in children. Research in this area can help define future directions for study and develop targeted intervention strategies in the pediatric population. The aim of this review is to examine the relationship between OS, antioxidant cofactor micronutrients, and cognitive outcomes in childhood obesity and to explore mechanisms, evidence, and therapeutic opportunities. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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12 pages, 1007 KB

Open AccessReview

Pathogenesis-Guided Biomarker Assessment: A Shift in Prostate Cancer Diagnostics

by Jessica M. Logan, Victoria Malone, John J. O’Leary and Doug A. Brooks

Int. J. Mol. Sci. 2025, 26(24), 11786; https://doi.org/10.3390/ijms262411786 - 5 Dec 2025

Viewed by 408

Abstract

Despite prostate cancer being one of the most common malignancies in men, its pathological diagnosis remains plagued by inter-observer variability and diagnostic ambiguity. Traditional morphological assessment and currently available biomarkers such as PSA (Prostate-Specific Antigen), AMACR (Alpha methylacyl CoA racemase), and p63 suffer [...] Read more.

Despite prostate cancer being one of the most common malignancies in men, its pathological diagnosis remains plagued by inter-observer variability and diagnostic ambiguity. Traditional morphological assessment and currently available biomarkers such as PSA (Prostate-Specific Antigen), AMACR (Alpha methylacyl CoA racemase), and p63 suffer from poor specificity and clinical reliability. In this review, we present a pathogenesis-guided biomarker discovery strategy that led to the development of a clinically validated biomarker panel—Appl-1, Sortilin, and Syndecan-1. These biomarkers, which reflect fundamental biological processes within the endosome–lysosome system, offer improved diagnostic precision and prognostic utility for patients with prostate cancer. This review discusses the rationale behind their discovery, the multidisciplinary approach that enabled it, the evidence supporting their use, and their implementation in U.S. clinical practice as a lab-developed test (LDT). We propose this approach as a new diagnostic standard that bridges mechanistic insight with real-world application. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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34 pages, 2407 KB

Open AccessReview

Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes

by Amalia Kotsifaki, Georgia Kalouda, Efthymios Karalexis, Martha Stathaki, Georgios Metaxas and Athanasios Armakolas

Int. J. Mol. Sci. 2025, 26(23), 11599; https://doi.org/10.3390/ijms262311599 - 29 Nov 2025

Viewed by 973

Abstract

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such [...] Read more.

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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27 pages, 1578 KB

Open AccessReview

Comprehensive Liquid Biopsy Approaches for the Clinical Management of Lung Cancer Using Multiple Biological Matrices

by Areti Strati, Martha Zavridou, Kostas A. Papavassiliou and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2025, 26(23), 11304; https://doi.org/10.3390/ijms262311304 - 22 Nov 2025

Cited by 2 | Viewed by 873

Abstract

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in both men and women. It is broadly classified into two main histological subtypes, with non-small cell lung cancer (NSCLC) being the most prevalent, accounting for approximately 85–90% [...] Read more.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in both men and women. It is broadly classified into two main histological subtypes, with non-small cell lung cancer (NSCLC) being the most prevalent, accounting for approximately 85–90% of all cases. Liquid biopsy refers to the analysis of tumor-derived material circulating in body fluids. This minimally invasive technique can be performed repeatedly over time and enables the detection of a tumor’s genomic profile without tissue samples. Liquid biopsies have the potential to identify biomarkers across different lung cancer subtypes that may be associated with early detection, prognosis, and prediction of response to targeted therapies. In this context, bioinformatics tools play a critical role in analyzing large-scale, high-dimensional omics datasets, which can be transformed into clinically meaningful insights. This article emphasizes the significance of prognostic, predictive, and diagnostic biomarkers in lung cancer, which can be detected in various biological fluids. Furthermore, it highlights how integrating bioinformatics approaches can facilitate the development of a personalized molecular profile, ultimately supporting individualized treatment strategies for each patient. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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28 pages, 1765 KB

Open AccessReview

The Role of mRNA Alternative Processing in Mammalian Neurodevelopment

by Xian Liu, Jian Zuo, Guicheng Zhang, Xiaoyu Han and Yao Tian

Int. J. Mol. Sci. 2025, 26(22), 11075; https://doi.org/10.3390/ijms262211075 - 16 Nov 2025

Viewed by 1013

Abstract

The mammalian brain undergoes a series of orderly developmental events, including neurogenesis, neuronal migration, axon guidance, and synaptic connection. These neurodevelopmental mechanisms have traditionally been characterized through studies focused on transcriptional control; however, a growing body of evidence highlights the critical roles of [...] Read more.

The mammalian brain undergoes a series of orderly developmental events, including neurogenesis, neuronal migration, axon guidance, and synaptic connection. These neurodevelopmental mechanisms have traditionally been characterized through studies focused on transcriptional control; however, a growing body of evidence highlights the critical roles of co- or post-transcriptional steps like alternative splicing, alternative polyadenylation, and RNA chemical modification in orchestrating brain development. This review discusses the recent progress made toward understanding the influence of alternative mRNA processing on neurodevelopment, including three aspects: the key mRNA processing events that drive neuronal differentiation from stem/progenitor cells; the regulatory mechanisms that govern cell-type and stage-specific mRNA-processing patterns; and the neuropathological consequences of mRNA-processing dysregulation. By integrating these insights, we aim to deepen the understanding of how mRNA alternative processing influences neurodevelopment and its implications for neurological health. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 544 KB

Open AccessReview

MicroRNAs in Uterine Leiomyosarcoma: From Molecular Mechanisms to Clinical Applications

by Areti Kourti, Ioannis Kalogiannidis, Kali Makedou and Elisavet Georgiou

Int. J. Mol. Sci. 2025, 26(22), 10952; https://doi.org/10.3390/ijms262210952 - 12 Nov 2025

Viewed by 742

Abstract

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are [...] Read more.

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are currently available. This review summarizes recent evidence on the role of microRNAs (miRNAs) in the biology and clinical management of uLMS. Literature from molecular and translational studies was examined to identify dysregulated miRNAs, their target pathways, and potential diagnostic and therapeutic applications. uLMS displays a characteristic miRNA profile, including downregulation of tumor-suppressive miRNAs such as the miR-29 and miR-200 families and upregulation of oncogenic miRNAs including miR-21 and the miR-183~96~182 cluster, leading to activation of PI3K/AKT/mTOR signaling and epithelial–mesenchymal transition (EMT). Circulating and tissue miRNAs show promise as minimally invasive biomarkers for differentiating uLMS from leiomyomas, predicting prognosis, and guiding therapy. Emerging therapeutic approaches aim to restore the tumor-suppressive miRNAs or inhibit oncogenic ones using mimics or antagomiRs. Overall miRNAs represent critical regulators of uLMS pathogenesis and hold significant potential for precision diagnosis, prognostication, and targeted therapy, though larger validation studies and improved delivery systems are required before clinical translation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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26 pages, 1431 KB

Open AccessReview

Molecular and Clinical Insights into TP53-Mutated MDS and AML

by Erotokritos Georgantzinos and Theodoros Karantanos

Int. J. Mol. Sci. 2025, 26(22), 10818; https://doi.org/10.3390/ijms262210818 - 7 Nov 2025

Viewed by 3320

Abstract

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a distinct subgroup of myeloid neoplasms with unique biological and clinical features. The molecular alterations linked to TP53 mutations drive genomic instability and treatment resistance and ultimately lead to poor survival outcomes. [...] Read more.

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a distinct subgroup of myeloid neoplasms with unique biological and clinical features. The molecular alterations linked to TP53 mutations drive genomic instability and treatment resistance and ultimately lead to poor survival outcomes. The disease biology is further shaped by alterations in immune response within the bone marrow microenvironment and significant changes in cellular metabolism. Conventional treatments, including chemotherapy and hypomethylating agents +/− venetoclax, offer limited benefit, with high relapse rates and short remissions. Allogeneic bone marrow transplantation is the only curative approach, but the vast majority of patients relapse. Novel therapeutic approaches—ranging from p53 reactivation strategies to immunotherapy and targeted inhibition of specific signaling pathways—are under active investigation. Our review summarizes current knowledge on the molecular pathogenesis, prognostic implications, and therapeutic landscape of TP53-mutated MDS/AML and discusses ongoing challenges and opportunities for improving patient outcomes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 1931 KB

Open AccessReview

Factor VII-Activating Protease (FSAP) and Its Importance in Hemostasis—Part II: A Link Between FSAP, Blood Coagulation, and Fibrinolysis: A Narrative Review

by Iga Schachta, Ewa Żekanowska, Jan Styczyński, Joanna Murawska, Simona Lattanzi, Andrea M. Alexandre and Artur Słomka

Int. J. Mol. Sci. 2025, 26(21), 10709; https://doi.org/10.3390/ijms262110709 - 3 Nov 2025

Viewed by 651

Abstract

As a continuation of Part I on the structure and regulation of factor VII-activating protease (FSAP), this narrative review synthesizes mechanistic, translational, and limited clinical evidence to delineate FSAP’s roles at the interface of coagulation and fibrinolysis. Current evidence indicates that FSAP enhances [...] Read more.

As a continuation of Part I on the structure and regulation of factor VII-activating protease (FSAP), this narrative review synthesizes mechanistic, translational, and limited clinical evidence to delineate FSAP’s roles at the interface of coagulation and fibrinolysis. Current evidence indicates that FSAP enhances thrombin generation primarily via proteolytic inactivation of tissue factor pathway inhibitor (TFPI), whereas direct activation of factor VII (FVII) by FSAP appears weak or context-restricted. Beyond plasma proteins, FSAP can upregulate tissue factor (TF) in human macrophages, while platelet-related effects remain insufficiently substantiated. On the fibrinolytic axis, FSAP indirectly accelerates clot lysis by converting single-chain urokinase (scuPA) to its active two-chain form (tcuPA) and, less efficiently, by processing tissue-type plasminogen activator (tPA); in addition, selective cleavage of fibrinogen Aα and Bβ chains remodels clot architecture, yielding thinner fibers with higher density and increased susceptibility to proteolysis. Collectively, the data position FSAP as a context-sensitive modulator of thrombin generation and fibrin turnover. Key gaps include isoform specificity, in vivo cellular targets, and the quantitative contribution of the FSAP-TFPI and FSAP–fibrinogen–urokinase/tPA axes in human pathophysiology, which warrant focused mechanistic and clinical studies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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22 pages, 862 KB

Open AccessReview

Diagnostic Value of Serum Biomarkers in Endocrine Dysfunction, Neuronal Injury, and Inflammation Following Traumatic Brain Injury

by Maria Bouta and Martha Assimakopoulou

Int. J. Mol. Sci. 2025, 26(21), 10702; https://doi.org/10.3390/ijms262110702 - 3 Nov 2025

Viewed by 756

Abstract

Traumatic brain injury (TBI) constitutes one of the primary causes of mortality globally. While many survivors fully recover, others experience several chronic complications that, if left untreated, negatively affect the patient’s quality of life. Among these, post-traumatic hypopituitarism (PTHP) represents a common yet [...] Read more.

Traumatic brain injury (TBI) constitutes one of the primary causes of mortality globally. While many survivors fully recover, others experience several chronic complications that, if left untreated, negatively affect the patient’s quality of life. Among these, post-traumatic hypopituitarism (PTHP) represents a common yet poorly recognized condition. The subtle, non-specific nature of pituitary dysfunction symptomatology, its overlap with similar disorders subsequent to TBI, and the lack of sensitive diagnostic tools are the main factors resulting in underdiagnosis of PTHP. The aim of this review is to summarize the existing knowledge, potential clinical utility, and limitations of serum biomarkers that may serve as reliable, minimally invasive tools for assessing pituitary function in the post-TBI period or even predicting late-onset deficiencies. These biomarkers, originating from neuronal damage or the inflammatory response following pituitary injury, can be co-evaluated with basal levels of pituitary and target organs hormones to accurately establish the diagnosis of the condition. Additionally, this review also provides an overview of emerging biomarkers that are currently under investigation and may be incorporated into clinical practice in the future. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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28 pages, 1429 KB

Open AccessReview

Natural Compounds Targeting MAPK, PI3K/Akt, and JAK/STAT Signaling in Papillary Thyroid Cancer

by Michelle Carnazza, Nan Yang, Raj K. Tiwari, Jan Geliebter and Xiu-Min Li

Int. J. Mol. Sci. 2025, 26(21), 10498; https://doi.org/10.3390/ijms262110498 - 29 Oct 2025

Viewed by 1467

Abstract

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after [...] Read more.

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after surgery, with a five-year survival rate exceeding 90%. Nevertheless, recurrence can occur, and the ten-year survival rate for the advanced PTC is below 50%. Even after effective successful surgical intervention, many still require ongoing surveillance, additional treatment, and lifelong thyroid hormone replacement, while facing the potential adverse effects such as hormone fluctuations, surgical complications, and sequelae of radioactive iodine exposure. Naturally occurring compounds have demonstrated anti-cancer properties and hence the potential to be used as therapeutic options, impacting the same drivers and pathways involved in the tumorigenesis of thyroid cancer. This narrative review focuses on the natural compounds’ convergence on molecular nodes of PI3K/Akt, MAPK, and JAK/STAT to overcome therapeutic resistance and restore apoptosis, highlighting their potential in advanced and recurrent PTC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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26 pages, 4226 KB

Open AccessReview

Molecular Mechanisms of the Microbiota–Gut–Brain Axis in the Onset and Progression of Stroke

by Javier Caballero-Villarraso, Sara Pons-Villarta, Jerónimo Cruces-Párraga, Ainoa Navarrete-Pérez, Antonio Camargo, Juan Antonio Moreno, Isaac Túnez and Eduardo Agüera-Morales

Int. J. Mol. Sci. 2025, 26(20), 10071; https://doi.org/10.3390/ijms262010071 - 16 Oct 2025

Cited by 2 | Viewed by 2360

Abstract

The bidirectional relationship between the brain and gut microbiota has led to the concept of the microbiota–gut–brain axis. It refers to a system of bilateral communication that integrates neuronal, immunological, and metabolic signals, whose disruption has been linked to the pathogenesis of digestive, [...] Read more.

The bidirectional relationship between the brain and gut microbiota has led to the concept of the microbiota–gut–brain axis. It refers to a system of bilateral communication that integrates neuronal, immunological, and metabolic signals, whose disruption has been linked to the pathogenesis of digestive, metabolic, and neurological disorders, among others. Intestinal dysbiosis (an imbalance in the gut microbiota) can promote a proinflammatory and prothrombotic state, as well as dyslipidaemia and dysglycemia, that increase atherogenic risk and consequently the risk of stroke. Dysbiosis can also lead to neuroinflammatory and neurodegenerative effects, compromising the integrity of the blood–brain barrier and exacerbating brain injury after stroke. Specific bacterial profiles have been associated with varying levels of stroke risk, emphasising the role of gut microbiota-derived vasoactive metabolites such as Trimethylamine N-Oxide (TMAO), phenylacetylglnutamine (PAGln), and short-chain fatty acids (SCFAs), which may serve as biomarkers for stroke risk and severity. Gut microbiota also influences neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), involved in recovery after stroke. Research has explored the potential to modify the gut microbiota to either prevent stroke (by reducing risk) or improve outcomes (by decreasing severity and sequelae). Current scientific evidence supports the role of gut microbiota as a potential diagnostic and prognostic biomarker, as well as a therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 1827 KB

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The Role of Cadherin 17 (CDH17) in Cancer Progression via Wnt/β-Catenin Signalling Pathway: A Systematic Review and Meta-Analysis

by Bipusha Tha Shrestha, Yahui Feng, Aaron Lad, Anthony Bates, Jing Chen, Karen Brown, Feier Zeng and Ning Wang

Int. J. Mol. Sci. 2025, 26(20), 9838; https://doi.org/10.3390/ijms26209838 - 10 Oct 2025

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Abstract

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across [...] Read more.

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across tumour types, limiting the assessment of CDH17 as a biomarker or therapeutic target for Wnt pathway in cancer. In this study, we systematically review and meta-analyse the relationship between CDH17 and Wnt/β-catenin signalling in human cancers and evaluate whether CDH17 modulation affects tumour behaviour through Wnt-related mechanisms. Our search of Medline, Web of Science and Scopus identified five studies examining CDH17 expression in the Wnt/β-catenin pathway in vitro and in vivo. All five studies identified CDH17 as a key driver of canonical Wnt signalling, directly influencing cancer progression in hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). Meta-analysis (MA) showed that CDH17 inhibition consistently reduced Wnt/β-catenin downstream T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activity (MD = −1.32, 95% CI: −1.64 to −0.99, p < 0.00001). Narrative synthesis found that CDH17 suppression decreased total and nuclear β-catenin, phosphorylated glycogen synthase kinase-3 beta (GSK-3β), and cyclin D1 while increasing tumour suppressors, retinoblastoma (Rb) and p53/p21. These changes were associated with reduced proliferation, colony formation, migration, invasion and cell cycle arrest. In vivo, CDH17 suppression resulted in 80–95% tumour growth suppression (Mean Difference (MD) = −96.67, 95% CI: [−144.35, −48.98], p < 0.0001), with immunohistochemistry confirming cytoplasmic β-catenin sequestration and lower cyclin D1 levels. Collectively, these findings show CDH17 as a critical upstream effector sustaining Wnt/β-catenin signalling, cancer progression, tumour proliferation, stem cell properties, and metastasis, and support CDH17 inhibition as a promising therapeutic target across multiple cancer types. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 818 KB

Open AccessReview

Stem Cells and Cell-Free Therapies for Olfactory Epithelium Regeneration: Insights from Experimental Models

by Keun-Ik Yi, Ji-Hwan Park, Sung-Dong Kim, Sue Jean Mun and Kyu-Sup Cho

Int. J. Mol. Sci. 2025, 26(18), 9024; https://doi.org/10.3390/ijms26189024 - 16 Sep 2025

Viewed by 2737

Abstract

Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. [...] Read more.

Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. Olfactory impairment can be caused by the degeneration of olfactory receptor neurons in the nose and also by the degeneration of the olfactory bulb of the olfactory cortex. Several studies have shown that stem cells promote the regeneration of the olfactory neuroepithelium after permanent damage in anosmic mice. Transplanted adipose stem cells differentiated into olfactory receptor neurons and endothelial cells. Recently, cell-free approaches using stem cell-derived secretome and extracellular vesicles (EVs) have emerged as a safer, more controllable alternative. These vesicles contain biologically active cargo such as neurotrophins, cytokines, and microRNAs that promote neurogenesis and modulate inflammation. Although direct application in anosmia models remains limited, findings from related neural injury models suggest that secretome- and EV-based therapies may achieve comparable regenerative efficacy to stem cell transplantation. This review summarizes current evidence on the regenerative capacity of stem cells and their secretome or EVs as therapeutic strategies for olfactory epithelium regeneration. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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21 pages, 820 KB

Open AccessReview

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Pathophysiology, Clinical Patterns, and Therapeutic Challenges of Intractable and Severe Forms

by Tatsuro Misu

Int. J. Mol. Sci. 2025, 26(17), 8538; https://doi.org/10.3390/ijms26178538 - 2 Sep 2025

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Abstract

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in [...] Read more.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Patients with MOGAD often exhibit better recovery from acute attacks; however, their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody- or complement-mediated perivenous demyelinating pathology, in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign forms to tissue necrosis, even though MOGAD is not a mild disease. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe clinical forms are: (1) fulminant acute multifocal lesions or multiphasic ADEM transitioning to diffuse (Schilder-type) or tumefactive lesions; (2) cortical or subcortical lesions related to brain atrophy and/or refractory epilepsy (Rasmussen-type); (3) longitudinally extended spinal cord lesions severely affected with residual symptoms. In addition, it is cautious for patients refractory to acute stage early 1st treatment including intravenous methylprednisolone treatment and apheresis with residual symptoms and relapse activity with immunoglobulin and other 2nd line treatments including B cell depletion therapy. Persistent MOG-IgG high titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity, such as cerebrospinal fluid interleukin-6 and complement C5b-9, could be identified as promising markers of higher disease activity, worsening of disability, and poor prognosis, and used to identify signs of escalating treatment strategies. It is promising of currently ongoing investigational antibodies against anti-interleukin-6 receptor and the neonatal Fc receptor. Moreover, due to possible refractory issues such as the intrathecal production of autoantibody and the involvement of complement in the worsening of the lesion, further developments of other mechanisms of action such as chimeric antigen receptor T-cell (CAR-T) and anti-complement therapies are warranted in the future. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessCase Report

Novel Homozygous Variants in CIDEC and WRN in a Young Female with Lipodystrophy and Thyroid Cancer

by Nivedita Patni, Chao Xing, Chun-Yuan Huang, Rebecca J. Brown and Abhimanyu Garg

Int. J. Mol. Sci. 2026, 27(2), 646; https://doi.org/10.3390/ijms27020646 - 8 Jan 2026

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Abstract

Autosomal recessive familial partial lipodystrophy type 5 (FPLD5) due to a homozygous NP_001186481.1; p.E186* CIDEC variant has previously been reported in a 19-year-old female with diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Now, we report an 18-year-old Hispanic female who presented with FPL, along [...] Read more.

Autosomal recessive familial partial lipodystrophy type 5 (FPLD5) due to a homozygous NP_001186481.1; p.E186* CIDEC variant has previously been reported in a 19-year-old female with diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Now, we report an 18-year-old Hispanic female who presented with FPL, along with hirsutism, acanthosis nigricans, and marked insulin resistance, and was found to have an extremely rare homozygous variant in CIDEC (NM_001199623.2:c.224G>T; NP_001186552.1; p.Ser75Ile) by whole exome sequencing. She also harbored a novel homozygous variant in WRN (NM_000553.4:c.1856T>G; NP_000544; p.Leu619Arg). Both serine 75 of the CIDEC protein and leucine 619 of the WRN protein were well conserved across species. She developed an invasive papillary thyroid carcinoma at the age of 17 years. Our report confirms the previously reported association of the biallelic CIDEC variant with the FPL phenotype and also highlights the extremely rare possibility of co-occurrence of FPLD5 with thyroid cancer, a clinical feature of Werner syndrome. Thus, our patient may not only need surveillance for the metabolic complications of FPLD5, such as diabetes, hypertriglyceridemia, and hepatic steatosis, but also for WRN-associated neoplasms and features of premature aging. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics

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