International Journal of Molecular Sciences

2026

Jump to: 2025

21 pages, 774 KB

Open AccessReview

Transfer RNA Fragments in Diseases of Sensory Organs

by Nikita Gulati, Zhongyu Yang, Yan X. Lin, Hameed Sanusi, Bianca Gonda, Dylan C. McNally, Alaina Stellwag, Madison C. Holmes, Rabiba Chaudhary, Johannah Stevenson, Kelly Lepouski, Lanae Johnson-Kleinpeter, Sathyanarayanan Vaidhyanathan, Maria E. Solesio and Andrey Grigoriev

Int. J. Mol. Sci. 2026, 27(9), 4142; https://doi.org/10.3390/ijms27094142 - 6 May 2026

Viewed by 436

Abstract

Transfer RNA-derived fragments (tRFs) have been recently recognized for their multiple roles in gene expression, including modulation of translation, mRNA stability, and cellular signaling pathways. Sensory organs, such as the eyes, skin, and oral cavity, are continuously exposed to environmental stressors, including oxidative [...] Read more.

Transfer RNA-derived fragments (tRFs) have been recently recognized for their multiple roles in gene expression, including modulation of translation, mRNA stability, and cellular signaling pathways. Sensory organs, such as the eyes, skin, and oral cavity, are continuously exposed to environmental stressors, including oxidative stress, ultraviolet radiation, microbial challenges, and mechanical stimuli, making them particularly susceptible to dysregulation of RNA-mediated processes. This review comprehensively summarizes current evidence on the role of tRFs in sensory organ physiology and pathology with a focus on their involvement in key processes, such as angiogenesis, inflammation, immune regulation, and fibrosis. tRFs have been shown to influence critical signaling pathways that are central to diseases such as retinal neovascularization, inflammatory skin conditions, wound healing, tissue remodeling, etc. Despite these advances, the field remains limited by a lack of experimentally validated tRF-target interactions, as most available data rely on computational predictions. The findings from the literature emphasize the need for rigorous functional validation in disease-relevant models of tRFs in biofluids, such as saliva and serum, to support their potential as minimally invasive biomarkers. Further translational studies are required to fully elucidate their biological roles and explore their potential in diagnostic and therapeutic applications. Full article

► Show Figures

Figure 1

36 pages, 595 KB

Open AccessReview

Metabolic Myokines and Adipokines in the Follicular Microenvironment: Implications for Oocyte Competence and IVF Outcomes

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Ioannis Papapanagiotou, Athanasios Karpouzos, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Christina Trakateli, Nana Kojo Koranteng, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Int. J. Mol. Sci. 2026, 27(8), 3344; https://doi.org/10.3390/ijms27083344 - 8 Apr 2026

Viewed by 616

Abstract

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a [...] Read more.

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a complex network of signalling chemicals that regulate mitochondrial activity, steroidogenesis, oxidative balance, and cellular energy metabolism. Recently, metabolic hormones originating from adipose tissue and skeletal muscle, namely, adipokines and myokines, have received considerable focus as crucial regulators of ovarian physiology. Adiponectin, irisin, and the recently identified hormone asprosin have emerged as crucial metabolic regulators influencing granulosa cell activity, mitochondrial bioenergetics, insulin signalling pathways, and redox homeostasis inside the follicular niche. Adiponectin mostly provides metabolic protection by activating AMP-activated protein kinase (AMPK) and improving insulin sensitivity, which in turn enhances mitochondrial efficiency and steroidogenic function in granulosa cells. Irisin, derived from the breakdown of fibronectin type III domain-containing protein 5 (FNDC5), aids the developing oocyte by facilitating mitochondrial biogenesis, augmenting oxidative phosphorylation, and altering cellular defence mechanisms against oxidative stress. Conversely, asprosin has been associated with glucogenic signalling, metabolic stress, and probable mitochondrial malfunction, suggesting a possible relationship between systemic metabolic problems and negative reproductive consequences. Clinical and experimental research indicate that the levels of these metabolic regulators in follicular fluid may correlate with ovarian response, oocyte quality, fertilisation rates, and embryo development during in vitro fertilisation cycles. This review consolidates current molecular, cellular, and clinical information, clarifying the pathways by which adipokines and myokines influence follicular metabolism and impact oocyte competency. Understanding the metabolic connections between systemic endocrine signals and the follicular milieu may provide novel indicators for reproductive prognosis and provide new treatment targets to improve assisted reproduction outcomes. Full article

► Show Figures

Figure 1

18 pages, 2678 KB

Open AccessArticle

Normalization of GC-MS Metabolomics Data in Adherent Cells: A Practical Comparison of Approaches

by Ilya Yu. Kurbatov, Svyatoslav V. Zakharov, Olga I. Kiseleva, Viktoriia A. Arzumanian, Igor V. Vakhrushev, Roza Yu. Saryglar, Victoria D. Novikova, Yan S. Kim and Ekaterina V. Poverennaya

Int. J. Mol. Sci. 2026, 27(7), 3219; https://doi.org/10.3390/ijms27073219 - 2 Apr 2026

Viewed by 591

Abstract

Data compatibility remains a major challenge in metabolomics, as commonly used measures of biological material—such as sample weight or cell count—are often poorly reproducible. Here, we systematically evaluated practical normalization strategies for GC × GC-MS-based metabolomic profiling of two widely used model cell [...] Read more.

Data compatibility remains a major challenge in metabolomics, as commonly used measures of biological material—such as sample weight or cell count—are often poorly reproducible. Here, we systematically evaluated practical normalization strategies for GC × GC-MS-based metabolomic profiling of two widely used model cell lines: human hepatoblastoma (HepG2) and mesenchymal stromal cells (MSCs). We compared orthogonal biomass estimates, including total protein and double-stranded DNA quantified either directly in aliquots of the cell suspension lysate aliquots or in the post-extraction cell precipitate, alongside normalization based on extracted ion current (XIC). We also assessed three widely used extraction mixtures—methanol/chloroform/water (7:2:1); methanol/water (8:2); acetonitrile/isopropanol/water (3:3:2)—for metabolome coverage and normalization robustness. Under realistic biological variability, signal-to-biomass dependencies were moderate. In contrast, under strictly controlled conditions, DNA- and protein-based normalization yielded near-linear relationships with metabolite abundances (R² > 0.90), demonstrating that biological variability is the dominant source of dispersion rather than technical factors. Methanol/chloroform/water system provided the broadest metabolome coverage and strongest correlation with injected biomass. Based on these findings, we recommend normalization to total precipitate protein or DNA using the methanol/chloroform/water extraction protocol, with XIC as a complementary quality control metric. Full article

► Show Figures

Figure 1

27 pages, 558 KB

Open AccessReview

Translational Fidelity Decline in the Aging Oocyte and Embryo Development

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Ioannis Papapanagiotou, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Charalampos Tsimpoukelis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Christina Trakateli, Nana Kojo Koranteng, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Int. J. Mol. Sci. 2026, 27(6), 2614; https://doi.org/10.3390/ijms27062614 - 12 Mar 2026

Viewed by 916

Abstract

Female reproductive aging is associated with a progressive decline in oocyte competence and reduced success in assisted reproductive technologies. While chromosomal abnormalities, mitochondrial dysfunction, and DNA damage have been extensively studied, these mechanisms do not fully explain developmental arrest in chromosomally euploid embryos [...] Read more.

Female reproductive aging is associated with a progressive decline in oocyte competence and reduced success in assisted reproductive technologies. While chromosomal abnormalities, mitochondrial dysfunction, and DNA damage have been extensively studied, these mechanisms do not fully explain developmental arrest in chromosomally euploid embryos or the variability in embryo competence. Human oocytes enter a transcriptionally quiescent state during meiotic maturation and rely almost entirely on the regulated translation of stored maternal messenger RNAs to support fertilization and early embryonic development until zygotic genome activation. In this context, translational fidelity becomes a critical determinant of proteome integrity and cellular function. Age-related alterations affecting ribosomal RNA integrity, transfer RNA modification, aminoacylation accuracy, and translational regulatory networks may impair the precision, timing, and coordination of protein synthesis. These defects can disrupt essential processes such as spindle assembly, cytoskeletal organization, and early cleavage dynamics, ultimately compromising embryo viability despite chromosomal normality. In addition, the follicular microenvironment, including redox balance, metabolic support, and signaling pathways, plays a crucial upstream role in maintaining translational integrity. This review integrates mechanistic evidence from molecular, cellular, and developmental studies to propose that progressive decline in translational fidelity represents a fundamental and previously underrecognized driver of reproductive aging. Understanding translational control as a central regulator of oocyte competence may provide new insights into unexplained IVF failure and support the development of novel biomarkers and therapeutic strategies aimed at preserving reproductive potential. Full article

► Show Figures

Figure 1

18 pages, 483 KB

Open AccessArticle

FSH Receptor Asn680Ser Polymorphism Modulates Intrafollicular Nitric Oxide Bioavailability and Ovarian Responsiveness During IVF

by Charalampos Voros, Diamantis Athanasiou, Despoina Mavrogianni, Ntilay Soyhan, Georgia Panagou, Maria Sakellariou, Georgios Papadimas, Fotios Chatzinikolaou, Eleni Sivylla Bikouvaraki, Georgios Daskalakis and Kalliopi Pappa

Int. J. Mol. Sci. 2026, 27(5), 2452; https://doi.org/10.3390/ijms27052452 - 6 Mar 2026

Viewed by 531

Abstract

In vitro fertilisation (IVF) has significant hurdles due to individual differences in ovarian response during controlled ovarian stimulation. The Asn680Ser polymorphism of the follicle-stimulating hormone receptor (FSHR) is linked to varying ovarian sensitivity to FSH. However, its relationship with intrafollicular redox signalling remains [...] Read more.

In vitro fertilisation (IVF) has significant hurdles due to individual differences in ovarian response during controlled ovarian stimulation. The Asn680Ser polymorphism of the follicle-stimulating hormone receptor (FSHR) is linked to varying ovarian sensitivity to FSH. However, its relationship with intrafollicular redox signalling remains unclear. Nitric oxide (NO) is a crucial compound that functions inside follicles and participates in angiogenesis, steroidogenesis, and oocyte competence. This prospective observational research classified women undergoing IVF into Asn allele carriers (Asn/Asn and Asn/Ser) and Ser/Ser homozygotes, according to the FSHR Asn680Ser polymorphism. The groups were assessed according to follicular fluid nitric oxide metabolites (NO₂-NO₃), fertilisation results, ovarian response indicators, and hormonal profiles. No substantial variation was seen between baseline and trigger-day hormone levels. In contrast, Ser/Ser individuals had a significantly higher total count of recovered oocytes, an elevated number of metaphase II oocytes, and enhanced fertilisation outcomes relative to carriers. The Ser/Ser group demonstrated increased intrafollicular NO₂-NO₃ concentrations. This difference was not statistically significant. These results link FSH receptor genetics to functional follicular competence, indicating that the FSHR Asn680Ser polymorphism is associated with differing ovarian responsiveness during IVF and may affect intrafollicular nitric oxide bioavailability. Full article

► Show Figures

Figure 1

15 pages, 934 KB

Open AccessReview

The Emerging Role of Transcription Factor Spi-C in Macrophage Biology and Inflammatory Pathogenesis

by Md Zahidul Alam and Weihua Huang

Int. J. Mol. Sci. 2026, 27(4), 1730; https://doi.org/10.3390/ijms27041730 - 11 Feb 2026

Viewed by 606

Abstract

Spi-C is a member of the ETS (E26 transformation-specific) family of transcription factors, a group of proteins that regulate gene expression in animals by binding to specific DNA sequences. Spi-C has emerged as a central regulator of macrophage adaptation to iron exposure, inflammatory [...] Read more.

Spi-C is a member of the ETS (E26 transformation-specific) family of transcription factors, a group of proteins that regulate gene expression in animals by binding to specific DNA sequences. Spi-C has emerged as a central regulator of macrophage adaptation to iron exposure, inflammatory stress, and tissue injury. Studies show that Spi-C programs iron-recycling macrophages by promoting expression of key iron-handling genes, thereby supporting iron efflux, safe intracellular iron storage, and the development of red pulp macrophages critical for systemic iron recycling. Its expression is strongly induced by heme and iron, enabling macrophages to respond adaptively to increased heme turnover, whereas Spi-C deficiency leads to impaired iron recycling and pathological iron accumulation. Beyond iron homeostasis, Spi-C is increasingly recognized as a regulator of inflammatory disease, functioning as an anti-inflammatory and tissue-protective factor across multiple models, including lipopolysaccharide (LPS)–induced systemic inflammation and colitis, where Spi-C deficiency leads to enhanced cytokine production, increased tissue injury, and impaired repair. By integrating NF-κB-driven inflammatory cues with metabolic adaptation, Spi-C maintains macrophage homeostasis across tissues. This short review summarizes these known functions and provides a forward-looking perspective that Spi-C may also regulate macrophage susceptibility to ferroptosis, an iron-dependent form of cell death implicated in diverse inflammatory and degenerative conditions. Full article

► Show Figures

Figure 1

16 pages, 1641 KB

Open AccessArticle

A Proteomic Study of the Dual Oncogenic and Tumor-Suppressive Roles of SIRT3 in Lung and Breast Cancer Cell Lines

by Marisol Ayala Reyes, Diana Lashidua Fernández Coto, Ramiro Alonso Bastida, György Marko-Varga, Jeovanis Gil and Sergio Encarnación-Guevara

Int. J. Mol. Sci. 2026, 27(3), 1325; https://doi.org/10.3390/ijms27031325 - 28 Jan 2026

Viewed by 819

Abstract

Mitochondria play a crucial role in metabolism and energy production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They also help maintain intracellular calcium levels, facilitate communication between the nucleus and cytoplasm, detoxify reactive oxygen species (ROS), and regulate apoptosis. Reversible acetylation of [...] Read more.

Mitochondria play a crucial role in metabolism and energy production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They also help maintain intracellular calcium levels, facilitate communication between the nucleus and cytoplasm, detoxify reactive oxygen species (ROS), and regulate apoptosis. Reversible acetylation of mitochondrial proteins is a key post-translational modification influencing these processes, with the NAD⁺-dependent deacetylase SIRT3 being a major regulator. While SIRT3 has been described as a tumor suppressor in some contexts and as a tumor promoter in others, its role appears to be tissue- and metabolism-specific. Here, we compared the proteomic and acetylomic responses of lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7) cell lines to SIRT3 inhibition by 3-TYP. The two lines were selected based on distinct metabolic phenotypes and reported differences in basal SIRT3 abundance. Total proteome and mitochondrial-enriched fractions were analyzed separately for each cell line to avoid cross-line normalization bias. We identified 6457 proteins and 4199 acetylated peptides, revealing distinct pathway enrichments and acetylation changes after SIRT3 inhibition. A549 cells showed increased oxidative metabolism, while MCF7 cells exhibited metabolic reprogramming. These results indicate that the proteomic impact of SIRT3 modulation is strongly influenced by cellular metabolic context. All raw mass spectrometry data are publicly available in PXD063181. Full article

► Show Figures

Graphical abstract

22 pages, 6486 KB

Open AccessArticle

Regenerative Skin Remodeling by a Dual Hyaluronic Acid Hybrid Complex in Multimodal Preclinical Models

by Hyojin Roh, Ngoc Ha Nguyen, Jinyoung Jung, Jewan Kaiser Hwang, Young In Lee, Inhee Jung and Ju Hee Lee

Int. J. Mol. Sci. 2026, 27(2), 1027; https://doi.org/10.3390/ijms27021027 - 20 Jan 2026

Cited by 1 | Viewed by 1220

Abstract

Skin aging arises from extracellular matrix degradation, inflammation, and pigmentation dysregulation, yet most existing rejuvenation strategies target only a subset of these processes. This study investigated the multimodal rejuvenation potential of a dual hyaluronic acid compound (DHC), composed of low- and high-molecular-weight HA [...] Read more.

Skin aging arises from extracellular matrix degradation, inflammation, and pigmentation dysregulation, yet most existing rejuvenation strategies target only a subset of these processes. This study investigated the multimodal rejuvenation potential of a dual hyaluronic acid compound (DHC), composed of low- and high-molecular-weight HA integrated within a minimally cross-linked hybrid complex. In vitro assays using dermal fibroblasts, melanoma cells, and macrophages demonstrated that DHC enhanced fibroblast viability, collagen I/III and elastin production, antioxidant enzyme activity, and wound-healing capacity while reducing senescence markers. DHC markedly suppressed melanogenesis by downregulating the gene expression of MITF, TYR, and TRP1, and exerted strong anti-inflammatory activity by decreasing nitric oxide (NO) production and key cytokines, including TNF-α, IL-1β, IL-6, and CCL1. In a UVB-induced photoaging rat model, DHC reduced wrinkle depth, epidermal thickening, and melanin accumulation while improving elasticity, collagen density, hydration, and barrier integrity. Across these outcomes, DHC demonstrated biological effects that were comparable to, and in selected endpoints greater than, those of commonly used biostimulators and HA fillers in preclinical models. Collectively, these laboratory findings suggest that DHC exhibits broad preclinical bioactivity through combined biostimulatory, antioxidant, anti-inflammatory, and pigmentation-modulating effects. Further mechanistic and clinical studies are required to determine its translational relevance. Full article

► Show Figures

Figure 1

2025

Jump to: 2026

19 pages, 3514 KB

Open AccessArticle

Discrimination of Hard Ticks by Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP)

by Nandhini Perumalsamy, Rohit Sharma, Ayyanar Elango, Ananganallur Nagarajan Shriram and Manju Rahi

Int. J. Mol. Sci. 2026, 27(1), 285; https://doi.org/10.3390/ijms27010285 - 26 Dec 2025

Cited by 1 | Viewed by 1012

Abstract

Hard ticks are important vectors for several human and zoonotic pathogens, transmitting diseases such as Crimean–Congo hemorrhagic fever, Lyme disease, Kyasanur forest disease, Powassan virus disease, Tick-borne encephalitis, Rickettsiosis, and Anaplasmosis. Morphological identification of ticks relies on taxonomic keys but is often challenging [...] Read more.

Hard ticks are important vectors for several human and zoonotic pathogens, transmitting diseases such as Crimean–Congo hemorrhagic fever, Lyme disease, Kyasanur forest disease, Powassan virus disease, Tick-borne encephalitis, Rickettsiosis, and Anaplasmosis. Morphological identification of ticks relies on taxonomic keys but is often challenging due to damaged, engorged, or immature specimens and requires expertise. Molecular taxonomy can be a supplement to species identification and usually requires nucleotide sequencing of the genetic markers. PCR-RFLP is an important tool for tick identification and can be supplemented to the classical taxonomy. The current study focused on the morphological identification of important hard tick vectors from India, their phylogenetic positioning, and developing a PCR-RFLP based diagnostic tool for easy identification of hard tick vectors. The primer sets were designed to amplify the ITS-2 region from important tick vectors causing human and zoonotic diseases in India. These ticks were morphologically identified with taxonomical keys, and the extracted genomic DNA were used for ITS-2 based PCR amplification. The nucleotide sequences from each vector were used for their phylogenetic positioning. We obtained variable sizes of ITS-2 amplicons from each species and utilized the sequence for RFLP assays design. We have successfully shown PCR-RFLP based assays with two different restriction enzymes (Hae III & Rsa I) with specific restriction sites on the amplified regions. The PCR-RFLP tool showed different DNA fragment patterns on the agarose gel, specific for each hard tick vector. This study presents the phylogenetic positioning of Indian tick vectors and demonstrates the development and applicability of a molecular tool for their identification. Full article

► Show Figures

Graphical abstract

28 pages, 688 KB

Open AccessReview

Mass Spectrometry Quantification of Epigenetic Changes: A Scoping Review for Cancer and Beyond

by Rossana Comito, Agnese Mannaioli, Agen Peter Lunghi Msemwa, Francesca Bravi, Carlotta Zunarelli, Eva Negri, Emanuele Porru and Francesco Saverio Violante

Int. J. Mol. Sci. 2026, 27(1), 149; https://doi.org/10.3390/ijms27010149 - 23 Dec 2025

Viewed by 857

Abstract

Mass spectrometry has become an indispensable tool for the identification and quantification of epigenetic modifications, offering both high sensitivity and structural specificity. The two major classes of epigenetic modifications identified—DNA methylation and histone post-translational modifications—play fundamental roles in cancer development, underscoring the relevance [...] Read more.

Mass spectrometry has become an indispensable tool for the identification and quantification of epigenetic modifications, offering both high sensitivity and structural specificity. The two major classes of epigenetic modifications identified—DNA methylation and histone post-translational modifications—play fundamental roles in cancer development, underscoring the relevance of their precise quantification for understanding tumorigenesis and potential therapeutic targeting. In this scoping review, we included 89 studies that met the inclusion criteria for detailed methodological assessment. Among these, we compared pre-treatment workflows, analytical platforms, and acquisition modes employed to characterize epigenetic modifications in human samples and model systems. Our synthesis highlights the predominance of bottom-up strategies combined with Orbitrap-based platforms and data-dependent acquisition for histone post-translational modifications, whereas triple quadrupole mass spectrometers were predominant for DNA methylation quantification. We critically evaluate current limitations, including heterogeneity in validation reporting, insufficient coverage of combinatorial post-translational modifications, and variability in derivatization efficiency. Full article

► Show Figures

Figure 1

32 pages, 3296 KB

Open AccessReview

PAI-1: A Key Signal at the Crossroads of Stem Cell Differentiation and Senescence

by Jihan Ke, Youping Jiang, Zhiyong Cheng, Yulan Zhou, Jiaxu Lu, Bo Xu, Shouquan Yan and Jiafeng Wang

Int. J. Mol. Sci. 2026, 27(1), 86; https://doi.org/10.3390/ijms27010086 - 21 Dec 2025

Viewed by 1607

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is a central regulator of the fibrinolytic system and is increasingly recognized for its pivotal roles in a broad spectrum of physiological and pathological processes. In addition to its classical function in fibrinolysis, accumulating evidence highlights the involvement of [...] Read more.

Plasminogen activator inhibitor-1 (PAI-1) is a central regulator of the fibrinolytic system and is increasingly recognized for its pivotal roles in a broad spectrum of physiological and pathological processes. In addition to its classical function in fibrinolysis, accumulating evidence highlights the involvement of PAI-1 in cellular senescence, differentiation, fibrosis, thrombosis, and tumorigenesis. This review systematically summarizes recent advances in understanding the multifaceted biological functions of PAI-1, with a particular emphasis on its dual regulatory roles in cellular differentiation and senescence. Through manual curation and analysis of the literature, we constructed a PAI-1-centered signaling network associated with differentiation and further integrated this framework with known senescence-related pathways. This integrative approach aims to elucidate the crosstalk between differentiation and senescence mediated by PAI-1. By providing an in-depth overview of PAI-1 functions across various experimental models, this review offers a theoretical foundation for exploring its potential as a therapeutic target and presents novel perspectives for the development of intervention strategies for complex chronic diseases. Full article

► Show Figures

Figure 1

16 pages, 6424 KB

Open AccessArticle

The Myeloid Biomarker MS4A6A Drives an Immunosuppressive Microenvironment in Glioblastoma via Activation of the PGE2 Signaling Axis

by Jianan Chen, Qiong Wu, Anders E. Berglund, Robert J. Macaulay, James J. Mulé and Arnold B. Etame

Int. J. Mol. Sci. 2026, 27(1), 58; https://doi.org/10.3390/ijms27010058 - 20 Dec 2025

Cited by 1 | Viewed by 1153

Abstract

Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic [...] Read more.

Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic datasets (TCGA, CGGA, Ivy GAP, and Brain Immune Atlas) to systematically characterize the expression, prognostic relevance, and immune contexture of the myeloid biomarker membrane-spanning 4-domain A6A, MS4A6A, in GBM. Differential expression, survival, and pathway enrichment analyses were performed. Single-cell mapping and CellChat modeling delineated MS4A6A-associated TAM subpopulations, intercellular communication networks, and ligand–receptor signaling dynamics. Spatial transcriptomic validation and pharmacogenomic modeling were conducted to assess anatomic enrichment and therapeutic vulnerabilities. High MS4A6A expression predicted unfavorable survival and correlated with increased stromal and immune infiltration. Single-cell analyses localized MS4A6A predominantly to TAMs, especially Regulatory- and Ribo-TAM states enriched for antigen presentation, T-cell regulation, and ribosomal biogenesis pathways. CellChat analysis revealed that MS4A6A-high TAMs exhibited markedly enhanced communication with CD4⁺ T cells and Tregs through upregulated PGE₂–PTGER2/PTGER4, PECAM1–CD38, and THBS1–CD36 signaling axes, implicating MS4A6A in prostaglandin-driven immune suppression. Spatial profiling confirmed preferential localization of MS4A6A within perivascular and angiogenic niches. Pharmacogenomic prediction indicated that MS4A6A-high tumors were more sensitive to ERK, mTOR, and CDK4/6 inhibition. MS4A6A defines a macrophage-centered, immunosuppressive ecosystem in GBM, mediated by the activation of the PGE₂ signaling axis. These findings position MS4A6A both as a prognostic biomarker and as a potential therapeutic node linking myeloid reprogramming to actionable pathway vulnerabilities in glioblastoma. Full article

► Show Figures

Figure 1

21 pages, 8854 KB

Open AccessArticle

A Novel RANKL/RANK Inhibitor IMB-R38 Inhibits Osteoporosis Through Regulating Bone Metabolism

by Yuyan Zhang, Xinwei Wei, Ren Sheng, Guijun Yang, Xiaowan Han, Jingrui Wang, Chao Liu, Shunwang Li, Lijuan Lei, Weilian Jiang, Yang Lun, Shuyi Si, Jing Zhang and Yanni Xu

Int. J. Mol. Sci. 2025, 26(24), 12151; https://doi.org/10.3390/ijms262412151 - 17 Dec 2025

Cited by 2 | Viewed by 1325

Abstract

Osteoporosis is a systemic skeletal disease that severely impairs the health of the elderly population. The interaction between the receptor activator of the NF-κB ligand (RANKL) and its receptor RANK is critical for osteoclast differentiation and function. Therefore, targeting the RANKL/RANK interaction represents [...] Read more.

Osteoporosis is a systemic skeletal disease that severely impairs the health of the elderly population. The interaction between the receptor activator of the NF-κB ligand (RANKL) and its receptor RANK is critical for osteoclast differentiation and function. Therefore, targeting the RANKL/RANK interaction represents a promising strategy for osteoporosis. In this study, we employed a newly established yeast two-hybrid system based on RANKL/RANK interaction and identified IMB-R38, a novel benzamide compound that dose-dependently blocked RANKL/RANK interaction by inhibiting the growth of AH109 cells harboring pAD-RANKL/pBD-RANK plasmids in quadruple-dropout medium. IMB-R38 significantly suppressed osteoclast differentiation, disrupted F-actin ring formation, and downregulated the expression of osteoclast-specific genes, including NFATc1 and MMP9 in RANKL-induced RAW264.7 macrophages. IMB-R38 also promoted osteoblast differentiation by upregulating the expression of osteogenic genes. Importantly, in a dexamethasone (DXM)-induced osteoporotic zebrafish model, IMB-R38 significantly increased bone mineralization, with anti-osteoporosis efficacy superior to that of alendronate sodium (Alen). RT-qPCR assays showed that IMB-R38 significantly upregulated the mRNA expression of osteogenesis genes (Bmp2, Runx2a, Runx2b, Sp7, Alp, and Oc) while markedly downregulating that of the osteoclastogenesis genes (Mmp9, Mmp13, and Mmp2) compared with the DXM group. Mechanistically, an SPR assay confirmed that IMB-R38 directly binds with RANK but not RANKL to disrupt RANKL/RANK interaction. Furthermore, Asp168 of RANK was identified as a key amino acid that mediates both RANKL interaction and IMB-R38 binding. The inhibition of RANKL/RANK by IMB-R38 suppressed JNK phosphorylation and, consequently, osteoclast differentiation and function. Collectively, our findings identify IMB-R38 as a novel RANKL/RANK inhibitor with therapeutic potential for osteoporosis through its regulation of bone metabolism. Full article

► Show Figures

Figure 1

18 pages, 2145 KB

Open AccessArticle

Ploidy and Implantation Potential: Non-Invasive Small Non-Coding RNA-Based Health Assessment of Day 5 and 6 Blastocysts

by Angelika V. Timofeeva, Ivan S. Fedorov, Guzel V. Savostina, Alla M. Tarasova, Svetlana G. Perminova, Tatyana A. Nazarenko and Gennady T. Sukhikh

Int. J. Mol. Sci. 2025, 26(24), 12102; https://doi.org/10.3390/ijms262412102 - 16 Dec 2025

Viewed by 715

Abstract

A predominant etiological factor in implantation failure and early pregnancy loss is embryonic chromosomal abnormalities. The current clinical standard for determining embryonic ploidy is invasive preimplantation genetic testing. This procedure imposes mechanical stress on embryonic cells during trophectoderm biopsy and fails to significantly [...] Read more.

A predominant etiological factor in implantation failure and early pregnancy loss is embryonic chromosomal abnormalities. The current clinical standard for determining embryonic ploidy is invasive preimplantation genetic testing. This procedure imposes mechanical stress on embryonic cells during trophectoderm biopsy and fails to significantly improve live birth rates per transfer, likely due to its inability to evaluate the embryo’s implantation potential. Consequently, there is a clear need to develop a non-invasive method, suitable for routine clinical practice, that can simultaneously assess both the ploidy and implantation competence of a blastocyst prior to uterine transfer. Our research group was the first to achieve this by quantifying specific piwiRNAs (piR_016677, piR_017716, piR_020497, piR_015462) in spent culture medium. These data served as the foundation for logistic regression models tailored for day 5 blastocysts, day 6 blastocysts, and blastocysts irrespective of their developmental rate. These models demonstrated high diagnostic accuracy, with specificity ranging from 68% to 100% and sensitivity from 71% to 100%. The rationale for employing these molecules as biomarkers lies in their potential biological roles, which encompass maintaining genomic stability through LINE-1 regulation, as well as direct involvement in critical processes such as cell cycle control, spindle assembly, and cellular adhesion—all of which are imperative for successful implantation. Full article

► Show Figures

Figure 1

22 pages, 2973 KB

Open AccessArticle

Interplay Between DNA Polymerase, RNA Polymerase, and RNase H1 During Head-On Transcription–Replication Conflict

by Nadezhda A. Timofeyeva, Ekaterina I. Tsoi, Darya S. Novopashina, Nikita A. Kuznetsov and Aleksandra A. Kuznetsova

Int. J. Mol. Sci. 2025, 26(23), 11515; https://doi.org/10.3390/ijms262311515 - 27 Nov 2025

Cited by 1 | Viewed by 860

Abstract

Transcription–replication conflicts (TRCs) often occur in cells and cause DNA replication fork stalling. In this study, we investigated the interplay of RNA polymerase (RNAP), DNA polymerase, and RNase H1 (RH1) during head-on TRC in vitro with precise control over the reaction conditions. We [...] Read more.

Transcription–replication conflicts (TRCs) often occur in cells and cause DNA replication fork stalling. In this study, we investigated the interplay of RNA polymerase (RNAP), DNA polymerase, and RNase H1 (RH1) during head-on TRC in vitro with precise control over the reaction conditions. We show that it is a catalytically competent transcription elongation complex (TEC) that interferes with the action of both the Klenow fragment and full-length DNA Pol I. An incompetent RNAP complex with an R-loop stimulates the 3′→5′ exonuclease activity and pauses the DNA polymerase during head-on TRC. As RNAP advances along the DNA template, elongating the RNA, the head-on TRC is slowly overcome in our model system, likely through the reassociation of the displaced DNA polymerase with the nontemplate DNA strand upstream of RNAP. An isolated R-loop containing an 11-nt heteroduplex (R-loop-11) does not interfere with DNA replication by the Klenow fragment. For DNA Pol I, such an R-loop also does not stall replication but stimulates its 3′→5′ exonuclease activity. We demonstrate that a stalled Klenow fragment does not interfere with transcription, whereas a Klenow fragment moving along the TRC substrate towards RNAP alters the kinetics of RNAP. Stalled DNA Pol I does not stop RNAP but stimulates its endonuclease activity. We find that RH1 alone does not displace stalled RNAP from a competent TEC containing R-loop-11 and does not resolve the head-on TRC. On the other hand, RH1 displaces RNAP from the incompetent complex with the TRC substrate. This eliminates the stimulation of the 3′→5′ exonuclease activity of DNA polymerase during head-on TRC. Full article

► Show Figures

Figure 1

13 pages, 2920 KB

Open AccessArticle

Inactivation of the High-Affinity Ca²⁺ Uptake System Delays the Amiodarone-Induced Ca²⁺ Influx in Yeast Ogataea parapolymorpha

by Maria Kulakova, Maria Pakhomova, Victoria Bidiuk and Michael Agaphonov

Int. J. Mol. Sci. 2025, 26(23), 11386; https://doi.org/10.3390/ijms262311386 - 25 Nov 2025

Viewed by 579

Abstract

The antiarrhythmic drug amiodarone is toxic to yeast cells due to provoking Ca²⁺ entry into cytosol. Here we show that in Ogataea parapolymorpha, the loss of Cch1 or Mid1, which are the primary components of the high-affinity Ca²⁺ uptake system [...] Read more.

The antiarrhythmic drug amiodarone is toxic to yeast cells due to provoking Ca²⁺ entry into cytosol. Here we show that in Ogataea parapolymorpha, the loss of Cch1 or Mid1, which are the primary components of the high-affinity Ca²⁺ uptake system (HACS), leads to a delay in the rise of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) in response to amiodarone. This has negligible effect on the ability of the strain with the unaffected Ca²⁺ sequestration system to grow in the presence of amiodarone. Inactivation of the PMC1 gene encoding the Ca²⁺ ATPase involved in the cytosolic Ca²⁺ sequestration in the vacuole dramatically increases sensitivity to amiodarone, while inactivation of CCH1 or MID1 suppresses it. This correlates with a substantially lower [Ca²⁺]_cyt rise in response to amiodarone when the genes encoding the HACS components are inactivated in the mutant lacking Pmc1. Similarly to sodium dodecyl sulfate, which has also been shown to increase [Ca²⁺]_cyt, amiodarone causes activation of the Hog1 protein kinase involved in the cell cycle regulation. The role of HACS in the amiodarone-induced Ca²⁺ influx is discussed. Full article

► Show Figures

Figure 1

17 pages, 4010 KB

Open AccessArticle

Cellulose Plant-Derived Scaffolds as a Tool for Myometrium Modeling

by Anastasiia V. Sokolova, Ivan K. Kuneev, Yuliya A. Nashchekina and Alisa P. Domnina

Int. J. Mol. Sci. 2025, 26(22), 10995; https://doi.org/10.3390/ijms262210995 - 13 Nov 2025

Viewed by 866

Abstract

The myometrium is the smooth muscle layer of the uterus, whose dysfunctions are involved in various pathologies leading to infertility, such as adenomyosis and uterine fibroids. Developing relevant in vitro models of the myometrium is crucial for investigating the pathogenesis of these diseases. [...] Read more.

The myometrium is the smooth muscle layer of the uterus, whose dysfunctions are involved in various pathologies leading to infertility, such as adenomyosis and uterine fibroids. Developing relevant in vitro models of the myometrium is crucial for investigating the pathogenesis of these diseases. In this study, we propose a novel approach for cultivating mouse myometrial smooth muscle cells (SMCs) using plant-derived cellulose scaffolds. The scaffolds were obtained through the decellularization of green onion leaf, celery stalk, or bluegrass leaf, subsequently coated with collagen type I. We found that the structure of the green onion leaf scaffold provides unidirectional orientation of cultured cells, mimicking the tissue-specific organization of mouse myometrial SMCs in vivo. The mouse myometrial SMCs, cultured on this scaffold, proliferated, maintained viability up to 2.5 months, and retained the expression of the main markers of smooth muscle contractility (α-smooth muscle actin, transgelin, calponin, smooth muscle myosin heavy chains, connexin-43). To reproduce the native myometrium structure, a multilayered cultivation system was created. In a system of two overlaying scaffolds, cells also retained the viability and expression of smooth muscle contractility markers. The developed approach can be used for three-dimensional myometrium modeling to study the pathogenesis of myometrium-associated diseases. Full article

► Show Figures

Figure 1

25 pages, 1672 KB

Open AccessArticle

Antioxidant Status of Cyanobacteria Strains During Long-Term Cultivation in Nitrogen-Free Media

by Irina Maltseva, Aleksandr Yakoviichuk, Svetlana Maltseva, Maxim Kulikovskiy and Yevhen Maltsev

Int. J. Mol. Sci. 2025, 26(22), 10891; https://doi.org/10.3390/ijms262210891 - 10 Nov 2025

Cited by 2 | Viewed by 1099

Abstract

This study examines the antioxidant status of four Nostoc and Desmonostoc strains during long-term cultivation in nitrogen-depleted media. Growth rates, retinol and α-tocopherol content, fatty acid composition, and activities of antioxidant enzymes were analysed. The results showed that all tested strains adapted to [...] Read more.

This study examines the antioxidant status of four Nostoc and Desmonostoc strains during long-term cultivation in nitrogen-depleted media. Growth rates, retinol and α-tocopherol content, fatty acid composition, and activities of antioxidant enzymes were analysed. The results showed that all tested strains adapted to nitrogen limitation using various cellular mechanisms. Specifically, the strain Nostoc sphaeroides exhibited the highest specific growth rate and elevated glutathione peroxidase activity. The Nostoc commune and Desmonostoc caucasicum strains displayed higher superoxide dismutase activity, suggesting robust antioxidative capabilities. Additionally, Desmonostoc caucasicum exhibited unique adaptive strategies, such as elevated succinate dehydrogenase activity. Generally, fatty acid composition changes showed divergent lipid peroxidation vulnerabilities among the studied strains. Principal component analysis highlighted clear distinctions among the strains in terms of their antioxidant capacities and metabolic adjustments. High retinol content correlated positively with increased catalase activity and fatty acid saturation, whereas α-tocopherol concentration was linked to succinate dehydrogenase activity. The obtained results underscore the robustness of cyanobacterial antioxidant defence systems and highlight their metabolic adaptations under nitrogen deprivation. Understanding these responses offers insight into potential biotechnological applications, such as biofertilizers or therapeutics. Full article

► Show Figures

Figure 1

14 pages, 3482 KB

Open AccessArticle

Neuroprotective Effects and Mechanisms of Arecoline Against H₂O₂-Induced Damage in SH-SY5Y Cells

by Xiangfei Zhang, Jingwen Cui, Jing Sun, Fengzhong Wang, Bei Fan and Cong Lu

Int. J. Mol. Sci. 2025, 26(21), 10355; https://doi.org/10.3390/ijms262110355 - 24 Oct 2025

Cited by 1 | Viewed by 1393

Abstract

An overproduction of reactive oxygen species (ROS) creates oxidative stress that disrupts neuronal activity and contributes to the pathogenesis of neurodegenerative diseases. Arecoline, the predominant alkaloid component of Areca catechu L., is known for multiple biological activities, yet its involvement in neuronal oxidative [...] Read more.

An overproduction of reactive oxygen species (ROS) creates oxidative stress that disrupts neuronal activity and contributes to the pathogenesis of neurodegenerative diseases. Arecoline, the predominant alkaloid component of Areca catechu L., is known for multiple biological activities, yet its involvement in neuronal oxidative injury has not been fully clarified. This study investigated arecoline’s effect on hydrogen peroxide (H₂O₂)-induced toxicity in SH-SY5Y human neuroblastoma cells (SH-SY5Y). Arecoline pretreatment significantly improved cell viability and preserved plasma membrane integrity, accompanied by reduced lipid peroxidation and restoration of cellular antioxidant enzyme activities. Moreover, arecoline maintained mitochondrial membrane potential and suppressed apoptotic progression. At the molecular level, Arecoline stimulated nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression, concurrently diminishing Kelch-like ECH-associated protein 1 (Keap1) levels. In parallel, it altered the apoptosis profile by increasing B-cell lymphoma 2 (Bcl2) levels and decreasing Bcl-2-associated X protein (Bax) and total cysteine aspartate protease-3 (Caspase-3) protein expression. Collectively, the findings suggest that arecoline safeguards neurons against oxidative stress by simultaneously activating antioxidant defenses and restraining apoptosis. This study adds novel molecular evidence supporting the potential neuroprotective relevance of arecoline in oxidative stress-related neuropathology. Full article

► Show Figures

Figure 1

23 pages, 3542 KB

Open AccessArticle

Modulation of Nuclear Factor Kappa B Signaling and microRNA Profiles by Adalimumab in LPS-Stimulated Keratinocytes

by Aleksandra Plata-Babula, Wojciech Kulej, Paweł Ordon, Julia Gajdeczka, Martyna Stefaniak, Artur Chwalba, Piotr Gościniewicz, Tomasz Kulpok and Beniamin Oskar Grabarek

Int. J. Mol. Sci. 2025, 26(20), 10035; https://doi.org/10.3390/ijms262010035 - 15 Oct 2025

Cited by 2 | Viewed by 1180

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperactivation and dysregulated cytokine signaling, with nuclear factor kappa B (NF-κB), a master transcription factor that regulates immune and inflammatory gene expression, playing a central role. Adalimumab, a monoclonal antibody that inhibits tumor [...] Read more.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperactivation and dysregulated cytokine signaling, with nuclear factor kappa B (NF-κB), a master transcription factor that regulates immune and inflammatory gene expression, playing a central role. Adalimumab, a monoclonal antibody that inhibits tumor necrosis factor alpha (TNF-α), is widely used in psoriasis therapy, yet its molecular effects on NF-κB-associated genes and microRNAs (miRNAs) in keratinocytes remain insufficiently defined. In this study, immortalized human keratinocytes (HaCaT cells) were exposed to lipopolysaccharide (LPS) to induce inflammatory stress and treated with adalimumab for 2, 8, and 24 h. Transcriptome-wide profiling was performed using messenger RNA (mRNA) and miRNA microarrays, followed by validation with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Bioinformatic analyses included prediction of miRNA–mRNA interactions, construction of protein–protein interaction (PPI) networks, and gene ontology (GO) enrichment. Adalimumab reversed LPS-induced upregulation of NF-κB-associated genes, including inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB), interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 2 (TRAF2), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), and TNF alpha-induced protein 3 (TNFAIP3), with concordant changes observed at the protein level. Several regulatory miRNAs, notably miR-1297, miR-30a, miR-95-5p, miR-125b, and miR-4329, showed reciprocal expression changes consistent with anti-inflammatory activity. STRING analysis identified IKBKB as a central hub in the PPI network, while GO enrichment highlighted immune regulation, apoptosis, and NF-κB signaling. These findings demonstrate that adalimumab modulates NF-κB activity in keratinocytes through coordinated regulation of gene, protein, and miRNA expression, providing mechanistic insight into TNF-α blockade in psoriasis. Full article

► Show Figures

Figure 1

16 pages, 1475 KB

Open AccessReview

Redox Regulation of Endogenous Gasotransmitters in Vascular Health and Disease

by Giang-Huong Vu and Cuk-Seong Kim

Int. J. Mol. Sci. 2025, 26(18), 9037; https://doi.org/10.3390/ijms26189037 - 17 Sep 2025

Cited by 5 | Viewed by 2060

Abstract

Hydrogen sulfide (H₂S), nitric oxide (NO), and carbon monoxide (CO) are now recognized as key gasotranmitters that regulate vascular function, contributing to vasodilation, angiogenesis, inflammation control, and oxidative balance. Initially regarded as toxic gases, they are produced on demand by specific [...] Read more.

Hydrogen sulfide (H₂S), nitric oxide (NO), and carbon monoxide (CO) are now recognized as key gasotranmitters that regulate vascular function, contributing to vasodilation, angiogenesis, inflammation control, and oxidative balance. Initially regarded as toxic gases, they are produced on demand by specific enzymes, including cystathionine γ-lyase (CSE), endothelial nitric oxide synthase (eNOS), and heme oxygenase-1 (HO-1). Their activity is tightly controlled by redox-sensitive pathways. Reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide, modulate gasotransmitter biosynthesis at the transcriptional and post-translational levels. Moreover, ROS affect gasotransmitter availability through oxidative modifications, including thiol persulfidation, nitrosative signaling, and carbonylation. This redox regulation ensures a tightly coordinated response to environmental and metabolic cues within the vascular system. This review synthesizes the current understanding of redox–gasotransmitter interactions, highlighting how ROS modulate the vascular roles of H₂S, NO, and CO. Understanding these interactions provides critical insights into the pathogenesis of cardiovascular diseases and offers potential redox-targeted therapies. Full article

► Show Figures

Figure 1

32 pages, 1343 KB

Open AccessReview

Long Noncoding RNAs as Emerging Regulators of Seed Development, Germination, and Senescence

by Adrian Motor, Marta Puchta-Jasińska, Paulina Bolc and Maja Boczkowska

Int. J. Mol. Sci. 2025, 26(17), 8702; https://doi.org/10.3390/ijms26178702 - 6 Sep 2025

Cited by 4 | Viewed by 2928

Abstract

Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression during seed development and physiology. This review examines the diverse roles of lncRNAs in key stages of seed development, including embryogenesis, maturation, dormancy, germination, and aging. It integrates the current understanding [...] Read more.

Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression during seed development and physiology. This review examines the diverse roles of lncRNAs in key stages of seed development, including embryogenesis, maturation, dormancy, germination, and aging. It integrates the current understanding of the biogenesis and classification of lncRNAs, emphasizing their functional mechanisms in seeds, particularly those acting in cis and trans. These mechanisms include the scaffolding of polycomb and SWI/SNF chromatin remodeling complexes, the guidance of RNA-directed DNA methylation, the ability to function as molecular decoys, and the modulation of small RNA pathways via competitive endogenous RNA activity. This review highlights the regulatory influence of lncRNAs on abscisic acid (ABA) and gibberellin (GA) signaling pathways, as well as light-responsive circuits that control dormancy and embryonic root formation. Endosperm imprinting processes that link parental origin to seed size and storage are also discussed. Emerging evidence for epitranscriptomic modifications, such as m6A methylation, and the formation of LncRNA–RNA-binding protein condensates that maintain resting states and coordinate reserve biosynthesis are also reviewed. Advances in methodologies, including single-cell and spatial transcriptomics, nascent transcription, direct RNA sequencing, and RNA–chromatin interaction mapping, are expanding the comprehensive lncRNA landscape during seed development and germination. These advances facilitate functional annotation. Finally, possible translational research applications are explored, with a focus on developing lncRNA-based biomarkers for seed vigor and longevity. Full article

► Show Figures

Figure 1

24 pages, 2790 KB

Open AccessArticle

Anti-HMGB1 Antibody Therapy Ameliorates Spinal Cord Ischemia–Reperfusion Injury in Rabbits

by Genya Muraoka, Yasuhiro Fujii, Keyue Liu, Handong Qiao, Dengli Wang, Daiki Ousaka, Susumu Oozawa, Shingo Kasahara and Masahiro Nishibori

Int. J. Mol. Sci. 2025, 26(17), 8643; https://doi.org/10.3390/ijms26178643 - 5 Sep 2025

Cited by 2 | Viewed by 2134

Abstract

Spinal cord ischemia–reperfusion (SCI/R) injury remains a major clinical challenge with limited therapeutic options. High-mobility group box 1 (HMGB1), a proinflammatory mediator released during cellular stress, has been implicated in the pathogenesis of ischemia–reperfusion-induced neural damage. In this study, we investigated the neuroprotective [...] Read more.

Spinal cord ischemia–reperfusion (SCI/R) injury remains a major clinical challenge with limited therapeutic options. High-mobility group box 1 (HMGB1), a proinflammatory mediator released during cellular stress, has been implicated in the pathogenesis of ischemia–reperfusion-induced neural damage. In this study, we investigated the neuroprotective potential of the anti-HMGB1 monoclonal antibody (mAb) in a rabbit model of SCI/R injury. Male New Zealand White rabbits were anesthetized and subjected to 11 min of abdominal aortic occlusion using a micro-bulldog clamp following heparinization. Anti-HMGB1 mAb or control IgG was administered intravenously immediately after reperfusion and again at 6 h post-reperfusion. Neurological function was assessed at 6, 24, and 48 h after reperfusion using the modified Tarlov scoring system. The rabbits were euthanized 48 h after reperfusion for spinal cord and blood sampling. Treatment with anti-HMGB1 mAb significantly improved neurological outcomes, reduced the extent of spinal cord infarction, preserved motor neuron viability, and decreased the presence of activated microglia and infiltrating neutrophils. Furthermore, it attenuated apoptosis, oxidative stress, and inflammatory responses in the spinal cord, and helped maintain the integrity of the blood–spinal cord barrier. These findings suggest that anti-HMGB1 mAb may serve as a promising therapeutic agent for SCI/R injury. Full article

► Show Figures

Figure 1

22 pages, 513 KB

Open AccessReview

Unraveling NETs in Sepsis: From Cellular Mechanisms to Clinical Relevance

by Giulia Pignataro, Stefania Gemma, Martina Petrucci, Fabiana Barone, Andrea Piccioni, Francesco Franceschi and Marcello Candelli

Int. J. Mol. Sci. 2025, 26(15), 7464; https://doi.org/10.3390/ijms26157464 - 1 Aug 2025

Cited by 20 | Viewed by 6055

Abstract

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of [...] Read more.

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of chromatin DNA, histones, and granular proteins released by neutrophils through a specialized form of cell death known as NETosis. While NETs contribute to the containment of pathogens, their excessive or dysregulated production in sepsis is associated with endothelial damage, immunothrombosis, and organ dysfunction. Several NET-associated biomarkers have been identified, including circulating cell-free DNA (cfDNA), histones, MPO-DNA complexes, and neutrophil elastase–DNA complexes, which correlate with the disease severity and prognosis. Therapeutic strategies targeting NETs are currently under investigation. Inhibition of NET formation using PAD4 inhibitors or ROS scavengers has shown protective effects in preclinical models. Conversely, DNase I therapy facilitates the degradation of extracellular DNA, reducing the NET-related cytotoxicity and thrombotic potential. Additionally, heparin and its derivatives have demonstrated the ability to neutralize NET-associated histones and mitigate coagulopathy. Novel approaches include targeting upstream signaling pathways, such as TLR9 and IL-8/CXCR2, offering further therapeutic promise. Full article

► Show Figures

Figure 1

19 pages, 4046 KB

Open AccessArticle

TMAO Activates the NLRP3 Inflammasome, Disrupts Gut–Kidney Interaction, and Promotes Intestinal Inflammation

by Leyao Fang, Junxi Shen, Nenqun Xiao and Zhoujin Tan

Int. J. Mol. Sci. 2025, 26(15), 7441; https://doi.org/10.3390/ijms26157441 - 1 Aug 2025

Cited by 9 | Viewed by 2367

Abstract

Gut microbiota-derived trimethylamine N-oxide (TMAO) has been implicated in both intestinal and renal diseases; however, its specific role in modulating gut–kidney interactions remains unclear. This study aimed to investigate the effects of TMAO on gut–kidney crosstalk using a mouse model of diarrhea. Mice [...] Read more.

Gut microbiota-derived trimethylamine N-oxide (TMAO) has been implicated in both intestinal and renal diseases; however, its specific role in modulating gut–kidney interactions remains unclear. This study aimed to investigate the effects of TMAO on gut–kidney crosstalk using a mouse model of diarrhea. Mice were divided into four groups: normal, model, TMAO, and TMAO + model. The normal group received sterile water, while the other groups were administered adenine + Folium sennae, TMAO, or a combination of TMAO and adenine + Folium sennae. Samples were collected to assess morphological changes in the colon and kidney, evaluate the colonic mucosal barrier and renal function, and measure NLRP3 inflammasome activity and inflammatory cytokine levels in colonic and renal tissues. TMAO levels and the gut microbiota composition were analyzed using 16S rRNA sequencing. The model group exhibited altered stool morphology, which was further aggravated by TMAO intervention. Both the model and TMAO + model groups exhibited significant damage to intestinal and renal tissues, along with compromised intestinal mucosal barriers and impaired renal function compared to controls. Inflammatory markers were elevated in these groups, with the TMAO + model group showing the most pronounced increases. Correlation analysis indicated significant relationships among TMAO levels, inflammasome activation, and inflammatory cytokines. The genera Mucispirillum and Anaerotruncus negatively correlated with TMAO, whereas Parabacteroides and Parasutterella genera positively correlated with TMAO. In conclusion, TMAO plays a critical role in modulating gut–kidney crosstalk by promoting inflammation, disrupting mucosal and renal integrity, and altering the gut microbial ecosystem. Full article

► Show Figures

Figure 1

Journal Menu

Journal Browser

Advances in Cell and Molecular Biology

Share This Topical Collection

Editor

Topical Collection Information

Keywords

Published Papers (25 papers)

2026

Jump to: 2025

2025

Jump to: 2026

Further Information

Guidelines

MDPI Initiatives

Follow MDPI