International Journal of Molecular Sciences

19 pages, 1459 KB

Open AccessArticle

Structural Characterization of DDX23 5′ UTR Regulatory Elements and Their Targeting by LNA-Modified Antisense Oligonucleotides

by Polina Kamzeeva, Nikita Shepelev, Veronika Zabbarova, Vladimir Brylev, Alexey Chistov, Dmitriy Ryazantsev, Erik Kot, Darya Novopashina, Maria Rubtsova and Andrey Aralov

Int. J. Mol. Sci. 2025, 26(22), 11047; https://doi.org/10.3390/ijms262211047 - 14 Nov 2025

Abstract

Translation of mRNAs is a tightly regulated process in gene expression. In mRNA, the 5′ untranslated region (5′ UTR) controls ribosome recruitment and frequently contains structured elements that modulate translation efficacy. This study investigates stable structural motifs within the 5′ UTR of DDX23 [...] Read more.

Translation of mRNAs is a tightly regulated process in gene expression. In mRNA, the 5′ untranslated region (5′ UTR) controls ribosome recruitment and frequently contains structured elements that modulate translation efficacy. This study investigates stable structural motifs within the 5′ UTR of DDX23 mRNA, encoding a protein relevant for anticancer therapy, as potential regulators and targets for antisense oligonucleotides (ASOs). Despite bioinformatic predictions and transcriptomic validations suggesting RNA G-quadruplex (rG4) formation, comprehensive structural analysis using a light-up assay and CD, UV, and NMR spectroscopy revealed that most putative rG4-forming sequences do not fold into stable rG4 structures, although one of them exists in an equilibrium between rG4 and an alternative, likely hairpin, conformation. Reporter assays using a robust G4 stabilizer also argue against the significant regulatory role of rG4s in DDX23 mRNA translation. Instead, we identified and characterized a stable hairpin structure with potential regulatory function. Based on these findings, we designed fully locked nucleic acid (LNA)-modified ASOs to target this hairpin and regions flanking the upstream open reading frame (uORF) and start codon of the coding sequence. A reporter assay demonstrated that cap-proximal targeting achieved robust translation inhibition up to 80%. In contrast, targeting the efficiently translated uORF was ineffective, presumably due to steric hindrances from the ribosomal complex. The study yields crucial design principles for translation-regulating ASOs: avoid targeting regions shielded by efficient uORF translation and carefully tune ASO-RNA duplex stability to surpass endogenous structures without disrupting regulatory mechanisms. These findings provide insights into the regulation of DDX23 expression and establish a framework for developing ASO-based therapeutics with broad implications for mRNA targeting in anticancer applications. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

13 pages, 2311 KB

Open AccessArticle

Genome-Wide Identification and Functional Characterization of CesA10 and CesA11 Genes Involved in Cellulose Biosynthesis in Sugarcane

by Yi Xu, Nameng Qi, Yi Han, Liying Cai, Xue Wang, Heyang Shang, Qing Zhang and Jisen Zhang

Int. J. Mol. Sci. 2025, 26(22), 11046; https://doi.org/10.3390/ijms262211046 - 14 Nov 2025

Abstract

Cellulose is the primary component of plant cell walls, and its content is linked to the strength of plant stems. The cellulose synthase genes (CesA) are crucial for regulating cellulose biosynthesis. To examine the characteristics and functions of CesA genes in [...] Read more.

Cellulose is the primary component of plant cell walls, and its content is linked to the strength of plant stems. The cellulose synthase genes (CesA) are crucial for regulating cellulose biosynthesis. To examine the characteristics and functions of CesA genes in sugarcane, our study conducted a genome-wide analysis of the Saccharum officinarum LA-Purple genome. The results identified 10 CesA genes in the S. officinarum genome, which could be grouped into six categories. SoCesA10, SoCesA11, and SoCesA12 are clustered within the same subclass as genes involved in secondary cell wall synthesis in rice and Arabidopsis. Further transcriptome analysis of stems at different stages and sections showed that SoCesA10, SoCesA11, and SoCesA12 were highly expressed during mature stages. Among these, SoCesA10 and SoCesA11 showed differences in expression between species and organs. Their gene functions were also validated in rice, revealing that the expression of SoCesA10 and SoCesA11 was positively correlated with cellulose content. In summary, this study identified key cellulose biosynthesis genes, SoCesA10 and SoCesA11, in sugarcane and preliminarily confirmed their functions in rice, providing a foundation for breeding sugarcane with improved lodging resistance. Full article

(This article belongs to the Section Molecular Plant Sciences)

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19 pages, 6358 KB

Open AccessArticle

Biomarker Identification via Spatial Transcriptomics Profiling of Colorectal Cancer and Colorectal Cancer with Liver Metastasis Stem Cells

by Minho Lee, Seoin Han, Hak Chun Kim, Yujun Jung, Jeong-An Gim, Chang-Jin Kim and Dongjun Jeong

Int. J. Mol. Sci. 2025, 26(22), 11045; https://doi.org/10.3390/ijms262211045 - 14 Nov 2025

Abstract

Colorectal cancer (CRC) demonstrates favorable clinical outcomes when diagnosed at an early stage; however, the prognosis declines substantially following recurrence or distant metastasis. Increasing evidence indicates that cancer stem cells (CSCs) are pivotal contributors to tumor recurrence, metastatic dissemination, and therapeutic resistance. The [...] Read more.

Colorectal cancer (CRC) demonstrates favorable clinical outcomes when diagnosed at an early stage; however, the prognosis declines substantially following recurrence or distant metastasis. Increasing evidence indicates that cancer stem cells (CSCs) are pivotal contributors to tumor recurrence, metastatic dissemination, and therapeutic resistance. The present study aimed to identify CSC-associated biomarkers through spatial transcriptomic profiling of normal colonic mucosa, primary CRC, and liver metastatic tissues, and to evaluate their functional relevance in CRC progression. Spatial transcriptomic analysis revealed that CCN2 was preferentially enriched within CSC clusters of primary CRC tissues, whereas APOC2 was predominantly upregulated in liver-metastatic CSCs. Functional validation of CCN2 was performed by establishing CCN2-knockout HCT116 cell lines using the CRISPR-Cas9 system. Loss of CCN2 expression markedly attenuated cell proliferation, migration, invasion, and oxaliplatin resistance compared with control cells. Furthermore, immunohistochemical analysis of tissue microarrays demonstrated a significant positive correlation between CCN2 expression and CSC markers SOX2 and Nestin. Collectively, these findings suggest that CCN2 functions as a central regulator of stemness and malignant potential in CRC and may represent a promising therapeutic target to prevent recurrence and metastasis. Additional mechanistic studies are warranted to further elucidate the molecular pathways of CCN2 and to validate the role of APOC2 in liver-metastatic CRC stem cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

17 pages, 5291 KB

Open AccessArticle

Klf5a in Endoderm Promotes Pharyngeal Cartilage Morphogenesis

by Wanqiu Li, Zeyao Zhu, Ou Sha and Xia Wang

Int. J. Mol. Sci. 2025, 26(22), 11044; https://doi.org/10.3390/ijms262211044 - 14 Nov 2025

Abstract

Pharyngeal cartilage, derived from neural crest cells (NCCs), undergoes complex morphogenesis driven by signals from the pharyngeal endoderm. However, the molecular mechanisms governing NCC proliferation and differentiation in response to endoderm-derived signals remain poorly understood. Here, we investigate the role of klf5a, [...] Read more.

Pharyngeal cartilage, derived from neural crest cells (NCCs), undergoes complex morphogenesis driven by signals from the pharyngeal endoderm. However, the molecular mechanisms governing NCC proliferation and differentiation in response to endoderm-derived signals remain poorly understood. Here, we investigate the role of klf5a, a zinc-finger transcription factor expressed in pharyngeal endodermal pouches, in zebrafish pharyngeal cartilage development. Knockdown of klf5a using morpholinos minimally affected cranial NCC specification and migration but significantly impaired their proliferation and differentiation in the pharyngeal region. Notably, klf5a deficiency reduced expression of fgfbp2b, a modulator of FGF signaling, in the pharyngeal endoderm. Co-injection of klf5a mRNA rescued the cartilage defects, but injection of fgfbp2b mRNA alone failed to restore normal cartilage morphogenesis, suggesting that fgfbp2b is not the sole mediator of klf5a’s effects. These findings indicate that klf5a regulates endodermal signaling to direct NCC-derived pharyngeal cartilage formation, likely through multiple downstream targets including fgfbp2b. This study provides insights into the complex molecular network underlying craniofacial development and highlights potential therapeutic targets for craniofacial disorders. Full article

(This article belongs to the Section Molecular Biology)

13 pages, 1699 KB

Open AccessArticle

COL10A1 Overexpression Promotes Gastric Cancer Aggressiveness Through EMT and Major Oncogenic Pathways

by Laura G. Necula, Denisa L. Dragu, Lilia Matei, Ioana Pitica, Simona O. Dima, Coralia Bleotu, Carmen C. Diaconu and Mihaela Chivu-Economescu

Int. J. Mol. Sci. 2025, 26(22), 11043; https://doi.org/10.3390/ijms262211043 - 14 Nov 2025

Abstract

Gastric cancer (GC) remains a major cause of cancer-related mortality, with limited options for early detection and precision therapy. Collagen family members are increasingly recognized as key structural and regulatory components of the tumor microenvironment. Collagen type X alpha 1 chain (COL10A1 [...] Read more.

Gastric cancer (GC) remains a major cause of cancer-related mortality, with limited options for early detection and precision therapy. Collagen family members are increasingly recognized as key structural and regulatory components of the tumor microenvironment. Collagen type X alpha 1 chain (COL10A1) appears among the top overexpressed genes in GC and has been linked with tumorigenesis, but its functional role in GC has not been completely elucidated. The oncogenic potential of COL10A1 was assessed in vitro in GC cell lines using adenoviral-mediated overexpression. Functional assays were further performed to evaluate proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) markers. Intracellular signaling alterations were analyzed by phosphokinase protein profiling and protein–protein interaction network analysis. COL10A1 overexpression significantly increased proliferation and migration, while reducing GC cell apoptosis. It promotes EMT by up-regulating mesenchymal markers (N-cadherin, Vimentin, Snail/Slug) and suppressing epithelial markers such as E-cadherin and β-catenin. Additionally, COL10A1 overexpression activated oncogenic signaling pathways, including the JNK and MAPK cascades, increasing proliferation and tumorigenic potential. Our results showed that COL10A1 functions as a driver for tumor progression by promoting proliferation, migration, and invasion along with EMT through activation of important oncogenic pathways. These findings highlight its biological role in tumor progression and contribute to a better understanding of GC pathogenesis. Full article

(This article belongs to the Special Issue Advances in the Molecular Pathogenesis of Gastrointestinal Malignancies with Implications for Diagnosis and Therapy)

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33 pages, 1445 KB

Open AccessReview

Targeting the CD47–TSP1 Axis in Abdominal Aortic Aneurysm: A Novel Immunotherapeutic Approach

by Karolina L. Stępień, Katarzyna Janas and Stanisław Rojek

Int. J. Mol. Sci. 2025, 26(22), 11042; https://doi.org/10.3390/ijms262211042 - 14 Nov 2025

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive dilation and weakening of the abdominal aortic wall. Despite advances in surgical repair, rupture remains associated with mortality rates exceeding 65%, and no effective pharmacological therapy exists to prevent disease progression. [...] Read more.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive dilation and weakening of the abdominal aortic wall. Despite advances in surgical repair, rupture remains associated with mortality rates exceeding 65%, and no effective pharmacological therapy exists to prevent disease progression. Increasing evidence highlights chronic inflammation, extracellular matrix degradation, and immune dysregulation as central drivers of AAA pathogenesis. Among these mechanisms, the thrombospondin-1 (TSP1)–CD47 signaling axis has emerged as a critical upstream regulator of vascular inflammation. By engaging CD47, TSP1 promotes macrophage activation, impairs efferocytosis, and sustains a self-perpetuating inflammatory loop that accelerates tissue destruction. This positions the TSP1–CD47 pathway as more than a bystander in aneurysm biology, linking immune activation with structural failure of the aortic wall. The therapeutic relevance of this axis is underscored by the development of CD47-targeted agents in oncology, which restore phagocytosis and immune balance. Repurposing such strategies for vascular medicine, in combination with advanced drug delivery systems, offers a promising avenue for disease-modifying therapy in AAA. Notably, two targeted drug delivery approaches have been described: both employ bispecific targeting of CD47 in combination with a macrophage-specific marker, using immunotoxins encapsulated in liposomal carriers to enhance selectivity and therapeutic efficacy. By shifting focus from structural repair to immune modulation, targeting the TSP1–CD47 axis with these strategies has the potential to redefine the clinical management of this condition. Full article

(This article belongs to the Section Molecular Biology)

10 pages, 590 KB

Open AccessCommunication

Sterol Composition in the Lichens Lobaria pulmonaria and Lobaria retigera: Does Photobiont Matter?

by Julia N. Valitova, Venera R. Khabibrakhmanova, Vasiliy M. Babayev, Ajsylu F. Khajrullina, Oleg P. Gurjanov, Natalia I. Gazizova, Richard P. Beckett and Farida V. Minibayeva

Int. J. Mol. Sci. 2025, 26(22), 11041; https://doi.org/10.3390/ijms262211041 - 14 Nov 2025

Abstract

The lipid composition of the mycobint and photobiont symbiotic partners of lichenized ascomycetes varies greatly. The aim of this study was to compare the profile of the major sterols in two closely related lichens from the genus Lobaria with different photobionts. The three-component [...] Read more.

The lipid composition of the mycobint and photobiont symbiotic partners of lichenized ascomycetes varies greatly. The aim of this study was to compare the profile of the major sterols in two closely related lichens from the genus Lobaria with different photobionts. The three-component lichen Lobaria pulmonaria has two photobionts. While the main photobiont is the chlorophycean alga Symbiochloris reticulata, this lichen contains small amounts of the cyanobacterium Nostoc. By contrast, the cyanobacterium Nostoc is the main photobiont in Lobaria retigera. Relatively loosely bound sterols were extracted using a chloroform–methanol mixture, and subsequently, more tightly bound sterols by alkaline saponification. The initial chloroform–methanol extraction step indicated that ergosterol is the principal sterol in both species, with phytosterols constituting a minor fraction. However, the addition of an alkaline saponification step to the standard protocol of sterol extraction greatly increases the release of tightly bound phytosterols, such as campesterol, stigmasterol, and β-sitosterol from L. pulmonaria, but not from L. retigera. Therefore, the mycobionts and Nostoc mainly possess sterols extractable by the standard mixture of chloroform/methanol, while the chlorophycean algal photobiont contains tightly bound sterols. This observation could be important when studying the roles of sterols in the stress tolerance of lichens. Full article

(This article belongs to the Special Issue New Insights of Fungal and Plant Lipids: Structural Diversity, Metabolism and Applications)

19 pages, 5648 KB

Open AccessArticle

Phase-Dependent Transcriptional Reprogramming of Vitis vinifera During Pierce’s Disease Progression by Xylella fastidiosa Infection

by Raghuraman Pandiyan and Seonjoo Park

Int. J. Mol. Sci. 2025, 26(22), 11040; https://doi.org/10.3390/ijms262211040 - 14 Nov 2025

Abstract

Pierce’s disease (PD), caused by the xylem-limited bacterium Xylella fastidiosa, poses a significant threat to global grapevine (Vitis vinifera) production. Despite its economic importance, the dynamic molecular mechanisms underlying grapevine responses to infection remain poorly understood. This study re-analyzed the [...] Read more.

Pierce’s disease (PD), caused by the xylem-limited bacterium Xylella fastidiosa, poses a significant threat to global grapevine (Vitis vinifera) production. Despite its economic importance, the dynamic molecular mechanisms underlying grapevine responses to infection remain poorly understood. This study re-analyzed the publicly available RNA-seq dataset GSE152164 to characterize phase-dependent transcriptional reprogramming during PD progression. Differential expression analysis using DESeq2 identified 1093 differentially expressed genes (DEGs) during the early infection phase (Phase I) and 136 in the intermediate phase (Phase II), indicating a strong early defense response followed by transcriptional downregulation as symptoms progressed. Comparative analysis distinguished 991 Phase-I-specific and 34 Phase-II-specific genes, along with 167 infection-specific temporal DEGs, underscoring a coordinated early immune response and subsequent metabolic repression. Protein–protein interaction network analysis identified 21 high-confidence hub genes, including chitinase (VIT_16s0050g02220), thaumatin-like protein (VIT_02s0025g04250), and EDS1 (VIT_17s0000g07560), which represent core regulators of defense and stress adaptation pathways. Collectively, this study elucidates the transcriptional dynamics underlying V. vinifera responses to X. fastidiosa and provides valuable insights for developing disease-resistant cultivars to mitigate Pierce’s disease. Full article

(This article belongs to the Special Issue From Genes to Medicine: Exploring the Genetic and Biological Bases of Medicinal Plants)

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10 pages, 259 KB

Open AccessArticle

Prevalence of Torque Teno Virus (TTV) in Cervical Precursor Lesions and Cancer in Chilean Women

by Matías Guzmán-Venegas, Carolina Moreno-León, Cristian Andrade-Madrigal, Alejandra Román, Rancés Blanco, Iván Gallegos and Francisco Aguayo

Int. J. Mol. Sci. 2025, 26(22), 11039; https://doi.org/10.3390/ijms262211039 - 14 Nov 2025

Abstract

Torque teno virus (TTV) is a highly prevalent DNA virus in humans, but its role in carcinogenesis is not well understood. While human papillomavirus (HPV) is a well-established etiological agent in cervical cancer, co-infections with other viruses such as Epstein–Barr virus (EBV) or [...] Read more.

Torque teno virus (TTV) is a highly prevalent DNA virus in humans, but its role in carcinogenesis is not well understood. While human papillomavirus (HPV) is a well-established etiological agent in cervical cancer, co-infections with other viruses such as Epstein–Barr virus (EBV) or TTV may influence disease progression. We conducted a cross-sectional study using 94 formalin-fixed, paraffin-embedded (FFPE) cervical tissue samples. These specimens were collected from women with cervical intraepithelial lesions (CINI-III) or squamous cell carcinoma (SCC) at the Clinical Hospital of the University of Chile. After extracting DNA, we screened for TTV using real-time polymerase chain reaction (qPCR). Statistical analysis was performed using Fisher’s exact test. Of the 94 samples, 83 were positive for the human β-globin gene and included in the final analysis. TTV was detected in 12.0% (10/83) of these samples. Among the TTV-positive cases, the virus was most frequently detected in high-grade lesions (70.0%), followed by low-grade lesions (20.0%) and squamous cell carcinoma (10.0%). However, these differences were not statistically significant (p = 0.688). This is the first study to assess TTV prevalence in cervical lesions among Chilean women. Although we found no statistically significant associations, a higher frequency of TTV was detected in precursor lesions compared to SCC. Further studies are needed to understand the potential immunomodulatory role of TTV in cervical carcinogenesis. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

17 pages, 1884 KB

Open AccessArticle

Cryopreserved Tissue Biospecimens Offer Superior Quality for Whole-Genome Sequencing of Various Cancers Compared to Paired Formalin-Fixed Paraffin-Embedded Tissues

by Ken Dixon, Jeong-Hoon Lee, Ryan Miller, David Booker, DeLaney Anderson, Jeffrey Okojie, Matthew Kirkham, Eun Kyoung Lee, Chunyang Bao, Islam Oguz Tuncay, Jung-Ah Kim, Sangmoon Lee and Jared Barrott

Int. J. Mol. Sci. 2025, 26(22), 11038; https://doi.org/10.3390/ijms262211038 - 14 Nov 2025

Abstract

Whole-genome sequencing (WGS) is integral to precision oncology, yet most cancer biospecimens used for WGS are formalin-fixed paraffin-embedded (FFPE) due to their widespread availability in clinical practice. However, FFPE processing can degrade DNA quality. This study compares WGS outcomes from matched cryopreserved (CP) [...] Read more.

Whole-genome sequencing (WGS) is integral to precision oncology, yet most cancer biospecimens used for WGS are formalin-fixed paraffin-embedded (FFPE) due to their widespread availability in clinical practice. However, FFPE processing can degrade DNA quality. This study compares WGS outcomes from matched cryopreserved (CP) and FFPE tumor samples, hypothesizing that CP tissues yield superior sequencing quality and variant detection. Fifty matched pairs of CP and FFPE tumor samples spanning multiple cancer types were obtained from a biobank. DNA was extracted, and WGS was performed. We assessed sequencing quality metrics and variant analysis between the two preservation methods. Presequencing metrics favored CP tissue, with a significantly higher gDNA concentration, DIN, and DNA fragment size. The WGS results showed that the CP samples had a higher mean read depth and larger insert size. Although the mapping percentages were similar, FFPE exhibited higher tumor mutation burden (13.7 vs. 6.4 mutations/Mb) and lower concordance with CP in variant calls (43.5% overlap). CP samples detected more structural variants and enabled the improved identification of oncogenic driver mutations. Cryopreserved tissues consistently outperform FFPE in terms of DNA quality and WGS metrics, enabling the more accurate detection of clinically relevant mutations. These findings support prioritizing CP sample preservation for genomic profiling in cancer care. Full article

(This article belongs to the Special Issue Molecular Dialogues in the Tumor Microenvironment: Mechanisms, Methods and Therapeutic Implications)

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15 pages, 929 KB

Open AccessReview

Impact of Anabolic–Androgenic Steroid Abuse on the Cardiovascular System: Molecular Mechanisms and Clinical Implications

by Antoni Borowiec, Iga Waluszewska, Michał Jurkiewicz and Wioletta Szczurek-Wasilewicz

Int. J. Mol. Sci. 2025, 26(22), 11037; https://doi.org/10.3390/ijms262211037 - 14 Nov 2025

Abstract

Anabolic–androgenic steroids (AAS) are synthetic derivatives of testosterone that are used therapeutically but are frequently abused by athletes and individuals seeking to increase muscle mass. Their anabolic (promoting muscle growth) and androgenic (inducing masculine characteristics) effects result from androgen receptor activation in target [...] Read more.

Anabolic–androgenic steroids (AAS) are synthetic derivatives of testosterone that are used therapeutically but are frequently abused by athletes and individuals seeking to increase muscle mass. Their anabolic (promoting muscle growth) and androgenic (inducing masculine characteristics) effects result from androgen receptor activation in target tissues. However, chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death. This review provides an updated and integrative perspective on both the molecular and clinical aspects of AAS-induced cardiovascular toxicity, highlighting recent advances in understanding endothelial injury, oxidative stress, fibrosis, and arrhythmogenesis. Importantly, it emphasizes the emerging recognition of AAS abuse as a modifiable cardiovascular risk factor and discusses potential preventive and therapeutic strategies, including early cardiovascular screening and risk stratification. Understanding these mechanisms is essential for recognizing the clinical manifestations of AAS misuse and for improving cardiovascular risk assessment in affected individuals. These insights underscore the clinical significance of AAS abuse as a cardiovascular risk factor and the need for vigilant cardiac monitoring and early intervention in this population. Full article

(This article belongs to the Special Issue Molecular Research into Chronic Heart Failure)

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18 pages, 2054 KB

Open AccessReview

Mild Cognitive Impairment and Sarcopenia: Effects of Resistance Exercise Training on Neuroinflammation, Cognitive Performance, and Structural Brain Changes

by Valeria Oporto-Colicoi, Alexis Sepúlveda-Lara, Gabriel Nasri Marzuca-Nassr and Paulina Sepúlveda-Figueroa

Int. J. Mol. Sci. 2025, 26(22), 11036; https://doi.org/10.3390/ijms262211036 - 14 Nov 2025

Abstract

Mild cognitive impairment (MCI) and sarcopenia are prevalent age-related conditions that often coexist and share common mechanisms such as chronic inflammation, reduced neuroplasticity, and impaired muscle function. Resistance exercise training (RET) has emerged as a promising non-pharmacological strategy capable of addressing both physical [...] Read more.

Mild cognitive impairment (MCI) and sarcopenia are prevalent age-related conditions that often coexist and share common mechanisms such as chronic inflammation, reduced neuroplasticity, and impaired muscle function. Resistance exercise training (RET) has emerged as a promising non-pharmacological strategy capable of addressing both physical and cognitive decline. The aim of this narrative review is to synthesize preclinical and clinical evidence on the effects of RET in older adults with MCI and sarcopenia, with a specific focus on its impact on neuroinflammation, cognitive performance and structural brain changes. At the molecular level, RET activates anabolic pathways, including PI3K/Akt/mTOR, enhances neurotrophic support via BDNF, NT-3, and IGF-1, and promotes hippocampal neurogenesis through exercise-induced myokines such as irisin and cathepsin B. RET also exerts immunomodulatory actions by shifting microglia toward anti-inflammatory M2 phenotypes, attenuating reactive astrogliosis, and supporting oligodendrocyte precursor cell differentiation, thereby improving myelin integrity. Neuroimaging studies consistently report preservation of hippocampal and precuneus gray matter, as well as improved white matter connectivity following RET. Clinically, RET has demonstrated significant and sustained improvements in executive function, memory, and global cognition, with effects persisting for up to 18 months. Collectively, RET represents a multifaceted intervention with the potential to delay progression from MCI to Alzheimer’s disease by integrating neuroprotective, anti-inflammatory, and anabolic effects. Standardization of RET protocols and identification of biomarkers of responsiveness are needed to optimize its role within multimodal dementia-prevention strategies. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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14 pages, 4228 KB

Open AccessArticle

Room Temperature UV Photodetector Based on Aero-Titania

by Mircea Nicolaescu, Tudor Braniste, Corina Orha, Mina-Ionela Morariu, Sebastian Lehmann, Kornelius Nielsch, Ion M. Tiginyanu, Raluca Faur, Victor Zalamai, Carmen Lazau and Cornelia Bandas

Int. J. Mol. Sci. 2025, 26(22), 11035; https://doi.org/10.3390/ijms262211035 - 14 Nov 2025

Abstract

This research demonstrates, for the first time, the integration of aero-titania material in sensor devices. An innovative approach for the practical application of aero-titania (aero-TiO₂) materials in photodetectors and the characterization under ultraviolet irradiation was assessed. The fabrication of aero-materials was [...] Read more.

This research demonstrates, for the first time, the integration of aero-titania material in sensor devices. An innovative approach for the practical application of aero-titania (aero-TiO₂) materials in photodetectors and the characterization under ultraviolet irradiation was assessed. The fabrication of aero-materials was carried out through the atomic layer deposition (ALD) of titanium dioxide ultrathin layers on a sacrificial network consisting of zinc oxide micro-tetrapods. This process was followed by a selective etching of the sacrificial ZnO template and formation of aero-titania hollow micro-tetrapods. The obtained material has been characterized using UV-Vis spectroscopy, scanning electron microscopy (SEM), and X-ray diffraction (XRD) analysis. The development of photodetectors was achieved through the sequential spin-coating deposition of aero-TiO₂ onto an interdigitated ceramic electrode. The obtained results show that, for high-intensity ultraviolet, the maximum sensitivity was reached for the two-deposited-layer aero-TiO₂ sensor at about 23, since for the low-intensity UV the highest sensitivity was recorded for the one-deposited-layer aero-TiO₂ sensor at about 12. In terms of the responsivity, the highest response was obtained for the one-deposited-layer aero-TiO₂ sensor under low-intensity illumination, reaching about 1.23 × 10⁻⁴ A W⁻¹ cm⁻². Thus, the aero-TiO₂ structure demonstrates the practical viability and application potential of this emerging class of materials in advanced sensing technologies. Full article

(This article belongs to the Special Issue State-of-the-Art Electrochemical Reaction Technologies)

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13 pages, 1971 KB

Open AccessArticle

Metabolomics Provides Insight into the Chemical Characteristics Underlying Bioactivity Differences Among Various Parts of Atractylodes Chinensis (DC.) Koidz.

by Yehui Hu, Xiangui Mei, Yingying Cui, Zhenying Wang, Chuanzhi Kang and Shengci Fan

Int. J. Mol. Sci. 2025, 26(22), 11034; https://doi.org/10.3390/ijms262211034 - 14 Nov 2025

Abstract

Atractylodes chinensis (DC.) Koidz. (AK) is a kind of medicinal plant in the Asteraceae family, and its dried rhizomes have the functions of drying dampness, strengthening the spleen, dispelling wind and cold, and brightening the eyes. However, there remains insufficient development and utilization [...] Read more.

Atractylodes chinensis (DC.) Koidz. (AK) is a kind of medicinal plant in the Asteraceae family, and its dried rhizomes have the functions of drying dampness, strengthening the spleen, dispelling wind and cold, and brightening the eyes. However, there remains insufficient development and utilization of other portions of the plant. To reveal the chemical characteristics and bioactivity potential of different AK parts, this study adopted UPLC-QE-MS/MS-based widely targeted metabolomics to analyze the metabolic components in ethanol extracts of AK rhizomes, fibrous roots, stems and leaves, flowers, and seeds. We then compared the antioxidant activities of these AK parts. The results showed that the highest ethanol extraction rate was from the rhizomes, while the flowers showed the strongest antioxidant activity. A total of 165 metabolites were categorized into seven major categories that included organic acids, flavonoids, and coumarins. Among these, organic acids were found with higher content in stems and leaves, fibrous roots, and seeds, while flavonoids were higher in flowers. This study explored the chemical composition and preliminary bioactivities of different AK parts based on widely targeted metabolomics. The results confirmed that the non-medicinal AK parts have high utilization values, and provided a scientific basis for the further development and utilization of this promising medicinal plant. Full article

(This article belongs to the Special Issue Metabolomics of Medicinal Plants)

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19 pages, 2439 KB

Open AccessReview

The Inflammatory Cell Death in Diabetic Kidney Disease: Integrating Multifactorial Mechanisms into Novel Therapeutics

by Bin Fang, Wei Huang, Sijia Du, Yu Hao, Fangfang He and Chun Zhang

Int. J. Mol. Sci. 2025, 26(22), 11033; https://doi.org/10.3390/ijms262211033 - 14 Nov 2025

Abstract

In addition to apoptosis, inflammatory cell death modalities—including pyroptosis, necroptosis, ferroptosis, NETosis, and the integrated paradigm of PANoptosis—are now established as critical drivers of diabetic kidney disease (DKD) pathogenesis. This review summarizes how key inflammatory cell death molecular mediators—such as the NLRP3 inflammasome, [...] Read more.

In addition to apoptosis, inflammatory cell death modalities—including pyroptosis, necroptosis, ferroptosis, NETosis, and the integrated paradigm of PANoptosis—are now established as critical drivers of diabetic kidney disease (DKD) pathogenesis. This review summarizes how key inflammatory cell death molecular mediators—such as the NLRP3 inflammasome, the RIPK1/RIPK3/MLKL axis, executioner caspases, and gasdermin-D (GSDMD)—orchestrate the death of renal cells (podocytes, tubular cells, mesangial cells, endothelium), thereby propagating inflammation and fibrosis. Preclinical studies have demonstrated the efficacy of agents targeting these pathways, highlighting their therapeutic potential. Key challenges include achieving cell type-specific targeting, overcoming redundancy among cell death pathways, and improving the translational applicability of current models. Emerging solutions include the development of precise biomarkers, kidney-targeted delivery systems, and combination therapies that concurrently target multiple cell death axes. This review synthesizes evidence establishing inflammatory cell death as a cornerstone of DKD pathology and provides a conceptual framework to guide future research and therapeutic innovation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and the Link Between Obesity, Diabetes and Inflammation)

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16 pages, 1034 KB

Open AccessArticle

Dysfunction of the Autophagy System and MDM2–p53 Axis Leads to the Accumulation of Amyloidogenic Proteins in Angelman Syndrome Models

by Jacqueline Fátima Martins de Almeida, Martina Contestabile, Ilaria Tonazzini, Chiara De Cesari, Laura Baroncelli, Claudia Martini and Simona Daniele

Int. J. Mol. Sci. 2025, 26(22), 11032; https://doi.org/10.3390/ijms262211032 - 14 Nov 2025

Abstract

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin–proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal [...] Read more.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin–proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular/mice AS models, silenced for UB3A (UB3A⁻). The main findings are as follows: (i) autophagy was upregulated in UBE3A⁻ cells with respect to control cells; (ii) a dysregulation of the AKT/mTOR pathway, linked to autophagy/synaptic development, was evidenced in cellular/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A⁻ cells with respect to controls. Finally, UB3A⁻ cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A⁻ cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 2520 KB

Open AccessArticle

Dichloroacetic Acid Enhances Photodynamic Therapy-Induced Regulated Cell Death in PANC-1 Pancreatic Cancer Cell Line

by Adeolu S. Oluremi, Krishnaswamy Kannan and Nawab Ali

Int. J. Mol. Sci. 2025, 26(22), 11031; https://doi.org/10.3390/ijms262211031 - 14 Nov 2025

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late-stage diagnosis, dense stromal barriers, and resistance to conventional therapies. The tumor microenvironment (TME), marked by hypoxia, aberrant vasculature, and metabolic reprogramming, supports tumor persistence and immune evasion. Targeting metabolic and oxidative [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late-stage diagnosis, dense stromal barriers, and resistance to conventional therapies. The tumor microenvironment (TME), marked by hypoxia, aberrant vasculature, and metabolic reprogramming, supports tumor persistence and immune evasion. Targeting metabolic and oxidative vulnerabilities in the TME offers a promising strategy to improve treatment outcomes. This study evaluated the combined effects of photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA), a precursor to the natural photosensitizer protoporphyrin IX (PpIX), and dichloroacetic acid (DCA), a mitochondrial function modulator, in the KRAS-mutated PANC-1 pancreatic cancer cell line. The combination of 5-ALA–PDT and DCA significantly reduced cell viability compared with either treatment alone. Mechanistic analyses revealed activation of multiple regulated cell death pathways, including mitochondria-mediated apoptosis, immunogenic cell death (ICD), and ferroptosis. This was evidenced by increased reactive oxygen species (ROS), loss of mitochondrial membrane potential (ΔΨm), release of danger-associated molecular patterns (DAMPs) such as ATP, and lipid peroxidation. DCA amplified PDT-induced oxidative stress, overcoming redox defenses and enhancing ferroptotic and immunogenic responses. These findings suggest that combining DCA with PDT enhances multimodal cell death in PDAC, providing a rationale for further in vivo studies to validate this redox–metabolic approach to treating chemoresistant pancreatic tumors. Full article

(This article belongs to the Collection Feature Papers Collection in Biochemistry)

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16 pages, 2217 KB

Open AccessArticle

TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models

by Monsurat Gbadamosi, Giulia Romano, Michela Simbula, Giulia Canarutto, Linda Ottoboni, Stefania Corti and Fabian Feiguin

Int. J. Mol. Sci. 2025, 26(22), 11030; https://doi.org/10.3390/ijms262211030 - 14 Nov 2025

Abstract

The pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to extensive alterations in RNA metabolism and a broad number of neuronal transcripts. However, the key effectors linking TDP-43 dysfunction to synaptic defects remain [...] Read more.

The pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to extensive alterations in RNA metabolism and a broad number of neuronal transcripts. However, the key effectors linking TDP-43 dysfunction to synaptic defects remain unclear. In this study, using Drosophila and human iPSC-derived motoneurons, we identify Rab4 as a direct and conserved target of TDP-43, whose expression is necessary and sufficient to recover synaptic vesicle recycling, neuromuscular junction growth, and locomotor function in TDP-43-deficient motoneurons. Moreover, Rab4 activity promotes the presynaptic recruitment of futsch/MAP1B, a microtubule-associated protein also regulated by TDP-43, which autonomously supports synaptic growth and vesicle turnover. Together, these findings define a TDP-43/Rab4/futsch/MAP1B regulatory axis that couples endosomal dynamics to cytoskeletal assembly. Furthermore, this functionally coherent module provides a mechanistic basis for understanding how synaptic vulnerability is amplified in disease and offers a framework to identify key compensatory targets capable of sustaining neuronal function in the absence of TDP-43. Full article

(This article belongs to the Section Molecular Biology)

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23 pages, 787 KB

Open AccessReview

Targeting Cancer Through Thymoquinone: From Molecular Mechanisms to Clinical Prospects

by Nosayba Al-Damook, Molham Sakkal, Mostafa Khair, Walaa K. Mousa, Ghalia Khoder and Rose Ghemrawi

Int. J. Mol. Sci. 2025, 26(22), 11029; https://doi.org/10.3390/ijms262211029 - 14 Nov 2025

Abstract

Thymoquinone (TQ), the active compound in Nigella sativa (black seed), has shown promising effects against cancer in many laboratory studies. In this review, we explore how TQ works on different aspects of cancer, from stopping cancer cell growth and spread, to triggering cancer [...] Read more.

Thymoquinone (TQ), the active compound in Nigella sativa (black seed), has shown promising effects against cancer in many laboratory studies. In this review, we explore how TQ works on different aspects of cancer, from stopping cancer cell growth and spread, to triggering cancer cell death, reducing inflammation, and helping the immune system fight back. We also highlight how TQ may overcome one of the biggest problems in cancer treatment—chemoresistance. When used together with common treatments like chemotherapy, radiation, or immunotherapy, TQ has been shown to improve their effects and reduce harmful side effects in preclinical models. Our review further discusses how TQ affects cancer stem cells, the tumor environment, and gene regulation through epigenetics. While these findings are encouraging, the lack of human studies remains a major gap. We also address TQ’s limited absorption and suggest ways to improve its delivery in the body, such as using nanoparticles or other carriers. Through this review, we aim to show the wide-ranging potential of TQ as a natural compound that may help make cancer treatments more effective and better tolerated. We call for clinical studies to take this research further and bring TQ closer to use in real-world cancer care. Full article

(This article belongs to the Section Molecular Oncology)

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International Journal of Molecular Sciences

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