International Journal of Molecular Sciences

23 pages, 13646 KB

Open AccessArticle

Repetitive Compressive Loading Downregulates the Expression of Autophagy-Related Factors, Autophagy Capacity and Cellular Activity in Human Osteoarthritic Chondrocytes

by Satomi Sato, Hideaki Iwata, Takeaki Yamamoto, Shu Somemura, Masahiro Takemoto, Yuki Takahashi-Suzuki, Yodo Sugishita, Hiroto Fujiya, Naoki Haraguchi and Kazuo Yudoh

Int. J. Mol. Sci. 2026, 27(16), 7485; https://doi.org/10.3390/ijms27167485 (registering DOI) - 21 Aug 2026

Abstract

Mechanical stress is thought to be involved in the pathogenesis and pathophysiology of osteoarthritis (OA). However, much remains to be elucidated regarding how chondrocytes sense and respond to mechanical stress (stress sensing and response factors). Additionally, it still remains unclear whether there are [...] Read more.

Mechanical stress is thought to be involved in the pathogenesis and pathophysiology of osteoarthritis (OA). However, much remains to be elucidated regarding how chondrocytes sense and respond to mechanical stress (stress sensing and response factors). Additionally, it still remains unclear whether there are defensive responses and mechanisms to protect against pathological agents and mechanical stress in articular cartilage tissue. This study was designed to determine whether repetitive mechanical force, at physiologic levels, affects the expression of factors regulating autophagy such as the autophagy-related proteins ATG5, Beclin-1, and Parkin, and the autophagy process as well as cellular activity in cultured chondrocytes. Three-dimensional cultured tissue was generated from human chondrocytes using a collagen sponge scaffold. After physiological mechanical loading of the 3D cell–collagen sponge construct, comparative analyses of expression levels of ATG5, Beclin-1, and Parkin were performed in human chondrocytes. Chondrocyte activity and Transmission Electron Microscopy (TEM) analysis for detecting autophagy process were also analyzed with or without repetitive compressive loading. In chondrocytes, 60 min or 180 min repetitive compressive loading significantly decreased the expression of ATG5, Beclin-1 and Parkin in comparison with the non-loading group. TEM analysis indicated that, in normal chondrocytes of the non-loading group, the autophagy process was shown to be progressing. In contrast, repetitive loading decreased the number of autophagosomes and autolysosomes in chondrocytes. In addition, numerous degenerated organelles that had not undergone autophagy were observed within the chondrocytes under repetitive loading. The ATG5 and Beclin-1 proteins are known to play crucial roles in regulating cellular autophagy. Furthermore, repetitive mechanical loading caused a decreased expression of Parkin, a mitophagy regulator in chondrocytes. Our results indicate for the first time that a decrease in mitophagy, as well as cellular autophagy, in response to mechanical stress, even at the physiologic level, leads to the accumulation of defective mitochondria and abnormal cellular proteins, resulting in reduced chondrocyte activity and affecting the maintenance of cartilage tissue homeostasis, ultimately contributing to the progression of OA. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 17376 KB

Open AccessArticle

Spatial Metabolomics Reveals the Common and Compound-Specific Pharmacological Mechanisms of Two Alkaloids Against Infarcted Myocardium

by Zixuan Zhang, Yixuan Lin, Feng Gao, Na Zhang, Jingyi Jiao, Huoli Yin, Tianzhen Liang, Herong Cui, Dong Bai and Haimin Lei

Int. J. Mol. Sci. 2026, 27(16), 7484; https://doi.org/10.3390/ijms27167484 (registering DOI) - 21 Aug 2026

Abstract

Acute myocardial infarction (AMI) is a leading cause of death worldwide, characterised by systemic inflammation and metabolic disorders. Tetrahydropalmatine (THP) and berberine (BBR) are major alkaloids derived from Corydalis yanhusuo and Coptis chinensis, respectively, both of which have been shown to be [...] Read more.

Acute myocardial infarction (AMI) is a leading cause of death worldwide, characterised by systemic inflammation and metabolic disorders. Tetrahydropalmatine (THP) and berberine (BBR) are major alkaloids derived from Corydalis yanhusuo and Coptis chinensis, respectively, both of which have been shown to be cardioprotective; however, whether their mechanisms differ remains unclear. In this study, we systematically compared THP and BBR in treating AMI using integrated spatial metabolomics (AFADESI-MSI), untargeted metabolomics, lipidomics, and molecular biology. The results showed that both compounds improved cardiac function, reduced fibrosis, and suppressed inflammation. Multi-omics revealed that although both regulate glycerophospholipid metabolism, their pathway preferences and functional roles diverge: THP primarily affects linoleic acid and acetylcholine metabolism with a greater propensity to restore membrane structural integrity, whereas BBR targets ether phospholipids and sphingolipids with preferential anti-inflammatory lipid modulation. At the enzymatic level, both downregulated CHKα, PEMT, ChAT, and PDHA1. A key difference is that THP uniquely upregulated acetylcholinesterase (AChE) mRNA expression, an effect absent with BBR. Spatial metabolomics directly visualised that both compounds reverse the accumulation of pro-inflammatory lysophosphatidylcholines (LPCs) and restore structural phosphatidylcholines (PCs) in the infarct region, thereby re-establishing regional lipid homeostasis. To our knowledge, this is the first integrated multi-omics comparison to suggest shared and distinct mechanisms of THP and BBR in AMI. Notably, the differential regulation of AChE, as visualised by spatial omics, may serve as a molecular basis for understanding their distinct therapeutic features, although further validation at the protein and enzymatic activity levels is warranted. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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2 pages, 150 KB

Open AccessCorrection

Correction: Almeida et al. Diterpenes: Nature’s Hidden Gems of Immunomodulation. Int. J. Mol. Sci. 2025, 26, 2250

by Josiane Elizabeth Almeida, André Correa de Oliveira, Carlos Eduardo de Castro Alves, Selino Monteiro Costa Filho, Elaine Cristina Pacheco de Oliveira, Juliana Pavan Zuliani and Gemilson Soares Pontes

Int. J. Mol. Sci. 2026, 27(16), 7483; https://doi.org/10.3390/ijms27167483 (registering DOI) - 21 Aug 2026

Abstract

The following references, [11] and [13], have been retracted and should be removed from the original publication [...] Full article

(This article belongs to the Special Issue The Impact of Natural Bioactive Compounds on Human Health and Disease)

25 pages, 9696 KB

Open AccessArticle

Distinct Inflammation-Associated Microbiome Signatures in Pediatric Non-IgE-Mediated Food Allergy

by Maria-Teodora Coșoreanu, Gratiela Gradisteanu Pircalabioru, Irina-Oana Lixandru-Petre, Mara-Ioana Ionescu, Andreea Ioan, Eliza-Elena Cinteză and Felicia Galoș

Int. J. Mol. Sci. 2026, 27(16), 7482; https://doi.org/10.3390/ijms27167482 (registering DOI) - 21 Aug 2026

Abstract

Non-IgE-mediated food allergy is characterized by delayed gastrointestinal manifestations and the absence of reliable non-invasive biomarkers. Increasing evidence suggests that gut microbiota may contribute to this disease pathogenesis. The aim of this study was to characterize the gut microbiome composition in thirty pediatric [...] Read more.

Non-IgE-mediated food allergy is characterized by delayed gastrointestinal manifestations and the absence of reliable non-invasive biomarkers. Increasing evidence suggests that gut microbiota may contribute to this disease pathogenesis. The aim of this study was to characterize the gut microbiome composition in thirty pediatric patients diagnosed with non-IgE-mediated food allergy, in comparison to fifteen healthy controls children, and to investigate its association with fecal calprotectin, eosinophil-derived neurotoxin (EDN) and IgA. Gut microbiota profiling was performed by 16S rRNA gene sequencing targeting the V3–V4 region. Compared with healthy controls, higher mean relative abundances of Bacteroides, Faecalibacterium, Alistipes, Parabacteroides, and Sutterella were observed in patients. Conversely, healthy children showed higher mean relative abundances of Pseudobutyrivibrio, Roseburia, Bifidobacterium, Collinsella, Clostridium, Eubacterium, Streptococcus, and Barnesiella. Several genera (Escherichia–Shigella, Agathobacter, and Enterococcus/Streptococcus) were detected only in the allergy cohort. Shannon diversity was higher in patients compared to controls and in the subgroups of patients with elevated fecal calprotectin (p = 0.028), previous antibiotic exposure (p = 0.015), and atopic dermatitis (p = 0.021). Stratification according to inflammatory biomarkers identified a distinct inflammatory microbiome endotype characterized by increased fecal calprotectin and EDN together with enrichment of Veillonellaceae and depletion of Bifidobacteriaceae and Lachnospiraceae. Correlation analyses further revealed positive associations between Veillonella abundance and both fecal calprotectin and EDN. These findings suggest that pediatric non-IgE-mediated food allergy is characterized by distinct microbiome–inflammation relationships rather than a single dysbiotic signature. Full article

(This article belongs to the Special Issue Probiotics, Prebiotics, Synbiotics, and Gut Microbial Modulation in Intestinal Health and Disease)

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24 pages, 11627 KB

Open AccessArticle

Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI

by Nancy Sun, Tristan N. Samuels, Kyle Hoffman, Ridhwan Busari, Zain Nasir, Nicole Girard, Noah M. Reynolds and Ilka U. Heinemann

Int. J. Mol. Sci. 2026, 27(16), 7481; https://doi.org/10.3390/ijms27167481 (registering DOI) - 21 Aug 2026

Abstract

Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot–Marie–Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to [...] Read more.

Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot–Marie–Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT. Full article

(This article belongs to the Special Issue Rare Genetic Diseases: From Molecular Mechanisms to Therapeutic Strategies)

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23 pages, 1653 KB

Open AccessReview

The Clinical Value of NT-proBNP, sST2, and Galectin-3 in the Management of Heart Failure: From Diagnosis to Dynamic Monitoring: A Narrative Review

by Diana Andreea Fărcaș, Monica Tarcea, Maria Cristina Tătar, Anda Cerghizan, Călin Crăciun, Hajnal Finta, Florina Gliga and Claudia Bănescu

Int. J. Mol. Sci. 2026, 27(16), 7480; https://doi.org/10.3390/ijms27167480 (registering DOI) - 21 Aug 2026

Abstract

Heart failure management remains a critical clinical challenge. While modern neurohormonal therapies have significantly improved survival, standard clinical assessments often fail to capture the full complexity of underlying structural disease progression. To comprehensively synthesize the established literature regarding the biological and prognostic roles [...] Read more.

Heart failure management remains a critical clinical challenge. While modern neurohormonal therapies have significantly improved survival, standard clinical assessments often fail to capture the full complexity of underlying structural disease progression. To comprehensively synthesize the established literature regarding the biological and prognostic roles of NT-proBNP, soluble ST2 (sST2), and Galectin-3 (Gal-3) and, subsequently, to propose a hypothesis-generating multimarker framework for HF risk stratification. A narrative review of the literature (2006–2026) was conducted across PubMed, Scopus, and Google Scholar. The synthesis focused on the clinical utility, phenotypic specificities, and methodological limitations of evaluating NT-proBNP, sST2, and Gal-3 concentrations. Evidence from the literature confirms that while NT-proBNP remains the gold standard for acute hemodynamic assessment. sST2 and Gal-3 provide complementary insights into active biomechanical strain and interstitial fibrotic remodeling; however, prospective randomized clinical trials demonstrating that sST2- or Gal-3-guided management improves clinical outcomes remain lacking. Based on these established findings, we propose an investigational four-step multimarker framework spanning from acute diagnosis to dynamic outpatient monitoring. This framework hypothesizes that integrating these pathways can better identify high-risk phenotypes that remain undetected by natriuretic peptides alone. The synergistic application of NT-proBNP, sST2, and Gal-3 offers a deeper pathophysiological evaluation of HF. However, our proposed biomarker-guided framework represents a set of testable research hypotheses. It requires prospective randomized validation before integration into routine clinical protocols for therapeutic titration. Full article

(This article belongs to the Special Issue Neurohormones in Cardiac Fibrosis and Heart Failure)

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22 pages, 1296 KB

Open AccessArticle

Effects of Maternal Zinc Deficiency and Post-Weaning Zinc Status on Neuroendocrine Markers Associated with Pubertal Regulation in Female Rat Offspring

by Meltem Gumus, Buse Gunaydın-Turker, Nilufer Akgun-Unal, Elif Gulbahce-Mutlu, Saltuk Bugra Baltaci, Omer Unal, Rasim Mogulkoc and Abdulkerim Kasim Baltaci

Int. J. Mol. Sci. 2026, 27(16), 7479; https://doi.org/10.3390/ijms27167479 (registering DOI) - 21 Aug 2026

Abstract

This study investigated the effects of maternal zinc deficiency and post-weaning zinc status on neuroendocrine markers associated with pubertal regulation in female rat offspring. A total of 40 female rats were divided into four groups: zinc deficiency (G1; MZD + ZD), standard diet [...] Read more.

This study investigated the effects of maternal zinc deficiency and post-weaning zinc status on neuroendocrine markers associated with pubertal regulation in female rat offspring. A total of 40 female rats were divided into four groups: zinc deficiency (G1; MZD + ZD), standard diet (G2; MZD + SD), zinc supplementation (G3; MZD + ZnS), and control (G4; CON). Groups G1–G3 were obtained from mothers with zinc deficiency, while G4 was obtained from mothers fed a standard diet. The procedures lasted 45 days. GATAD1, kisspeptin, GnRH, and NPY gene expressions in hypothalamic tissues were analyzed by RT-PCR; serum kisspeptin, GnRH, FSH, LH, leptin, and NPY levels were analyzed by ELISA. The lowest GATAD1, kisspeptin, and NPY gene expressions were found in groups G1 and G2 (p < 0.05), while the lowest GnRH expression was found in group G1 (p < 0.05). Serum zinc, kisspeptin, GnRH, LH, and leptin levels were lowest in G1 (p < 0.05) and highest in G3 and G4 (p < 0.05). Similarly, FSH and NPY levels were low in G1 and G2 (p < 0.05), and high in G3 and G4 (p < 0.05). The findings suggest that maternal zinc deficiency negatively impacts puberty-related neuroendocrine markers, and that zinc supplementation may correct these markers. Full article

(This article belongs to the Special Issue Research Advances in Circuit Mechanisms of Neurodegenerative Diseases)

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Graphical abstract

45 pages, 1931 KB

Open AccessReview

ZBP1 in Neuroinflammation and Neurodegeneration: Z-Nucleic-Acid Sensing, RHIM Signalling and Therapeutic Targeting

by Matei Șerban, Corneliu Toader and Răzvan-Adrian Covache-Busuioc

Int. J. Mol. Sci. 2026, 27(16), 7478; https://doi.org/10.3390/ijms27167478 (registering DOI) - 21 Aug 2026

Abstract

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, [...] Read more.

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer’s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA–RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3–MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neuroinflammation)

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2 pages, 150 KB

Open AccessCorrection

Correction: Kim et al. The Tumorigenic Role of Circular RNA-MicroRNA Axis in Cancer. Int. J. Mol. Sci. 2023, 24, 3050

by Woo Ryung Kim, Eun Gyung Park, Du Hyeong Lee, Yun Ju Lee, Woo Hyeon Bae and Heui-Soo Kim

Int. J. Mol. Sci. 2026, 27(16), 7477; https://doi.org/10.3390/ijms27167477 - 21 Aug 2026

Abstract

After the publication of this review article [...] Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Genetics and Genomics 2023)

35 pages, 22214 KB

Open AccessArticle

Novel Cerium Phosphate–Citric Acid Nanocomposites for Biomedical Applications in Regenerative Medicine: In Vitro and In Vivo Study

by Ekaterina V. Silina, Natalia E. Manturova, Elena L. Chuvilina, Akhmedali A. Gasanov, Olga I. Andreeva, Elena B. Artyushkova, Mikhail P. Gladchenko, Aleksandr V. Ivanov, Victor T. Dudka, Sergey Y. Mironov, Daria D. Tkachenko, Anatoly V. Skalny, Alexey A. Tinkov, Natalia Y. Tabachkova and Victor A. Stupin

Int. J. Mol. Sci. 2026, 27(16), 7476; https://doi.org/10.3390/ijms27167476 - 21 Aug 2026

Abstract

The aim of the study was to synthesize nanocomposites based on cerium orthophosphate stabilized with citrate at different ratios for biomedical applications, and to evaluate its safety in different animal species. Nanocomposites were synthesized using four different initial mass ratios of Ce(NO₃ [...] Read more.

The aim of the study was to synthesize nanocomposites based on cerium orthophosphate stabilized with citrate at different ratios for biomedical applications, and to evaluate its safety in different animal species. Nanocomposites were synthesized using four different initial mass ratios of Ce(NO₃)₃ × 6H₂O to citric acid: 1:5 (Ce:5CA), 1:3 (Ce:3CA), 1:1 (Ce:1CA), and 1:0.5 (Ce:0.5CA). The obtained products were characterized by a series of physicochemical methods including X-ray diffraction, transmission electron microscopy, and IR spectroscopy. Biomedical studies of the sols were performed to evaluate redox activity and their effects on the metabolism and proliferation of human fibroblasts. Safety studies were carried out in different animal species, including determination of the acute toxicity of the selected nanocomposite following application to intact skin and intragastric administration, as well as determination of subchronic toxicity using a model of acute experimental full-thickness skin wounds. According to the physicochemical studies, all synthesized nanocomposites contained nanocrystals with bimodal dimensions (width 3–10 nm, length 15–40 nm) and diffraction peaks characteristic of CePO₄. IR spectroscopy demonstrated the formation of new chemical bonds. Antioxidant activity was observed for the Ce:3CA, Ce:1CA, and Ce:0.5CA samples, being most pronounced for Ce:1–0.5CA, whose antioxidant capacity exceeded that of ascorbic acid. In contrast, Ce:5CA exhibited pro-oxidant activity at all tested concentrations. Biocompatibility with human cells was demonstrated. Ce:0.5CA was identified as the most promising candidate for biomedical applications owing to its highest regenerative and antioxidant potential and its demonstrated safety in animals following topical and intragastric administration, as well as in wound models. Histomorphological examination of the internal organs supported the safety and potential of the developed nanocomposites for skin regeneration and wound healing. Full article

(This article belongs to the Special Issue Nanomaterials in Tissue Engineering and Regenerative Medicine: Recent Advances and Future Prospects)

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21 pages, 25648 KB

Open AccessArticle

Iron Oxide Nanozyme for Magnetothermal Activation of ER-TRPV1 Enables Efficient Intravesical Therapy of Bladder Cancer

by Galong Li, Dongyan Li, Bin Lan, Yuanyuan Cheng, Hongxia Liang, Wenli Zhang, Xiaopan Xu and Hongbing Lu

Int. J. Mol. Sci. 2026, 27(16), 7475; https://doi.org/10.3390/ijms27167475 - 21 Aug 2026

Abstract

Drug-mediated intravesical therapy is a widely used treatment approach for bladder cancer (BCa), which is limited by poor tumor accumulation and the toxicity of drugs. Herein, a facile approach utilizing magnetic hyperthermia therapy (MHT) for BCa treatment is reported through intravesical instillation of [...] Read more.

Drug-mediated intravesical therapy is a widely used treatment approach for bladder cancer (BCa), which is limited by poor tumor accumulation and the toxicity of drugs. Herein, a facile approach utilizing magnetic hyperthermia therapy (MHT) for BCa treatment is reported through intravesical instillation of tumor-targeting iron oxide nanoparticles (IONPs), which are coated with anti-FGFR3 antibodies for specific binding to FGFR3 overexpressed on BCa cells. The antibody coating significantly enhanced targeting ability and increased cancer cell uptake. Under an alternating magnetic field (AMF), the IONPs magnetothermally activated TRPV1 on the endoplasmic reticulum (ER) of BCa and induced Ca²⁺ overload in RT4 BCa cells. The magnetothermal treatment significantly upregulated the pro-apoptotic gene expression of Bax, Pro-caspase-3, and Cytc in RT4 cells, and downregulated the anti-apoptotic effector gene Bcl-2, ultimately causing augmented apoptosis in cancer cells. The application of intravesical FGFR3-targeting MHT successfully resulted in greater suppression of tumor growth and improved survival rate of mice, compared to the control, IONP, and AMF-treated groups. These results hold significant potential as a transformative modality toward BCa therapeutic application. Full article

(This article belongs to the Special Issue Translational Insights in Solid Tumors: Bridging Molecular Mechanisms to Therapeutic Advances)

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23 pages, 10279 KB

Open AccessArticle

Cognition-Linked Monocyte State Reveals Altered Myeloid–Lymphoid Coordination in Neuro-PASC

by Barbara A. Hanson, Andrew C. Cogswell, Melissa Lopez, Janet Miller, Kristen L. Knutson, Mercedes R. Carnethon and Igor J. Koralnik

Int. J. Mol. Sci. 2026, 27(16), 7474; https://doi.org/10.3390/ijms27167474 - 21 Aug 2026

Abstract

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of [...] Read more.

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of peripheral blood immune cells from older adult (>55 years) individuals with and without NP to evaluate relationships with objective cognitive performance. NP participants showed reduced numbers of blood monocytes with increased mitochondrial superoxide, indicating an altered monocyte mitochondrial redox state. Higher peripheral capillary oxygen saturation (SpO₂) was associated with better processing speed in NP participants. Monocyte transcriptional analyses identified mitochondrial adenosine triphosphate (ATP) synthase/Complex V (Complex V) pathway associated with cognitive performance in people without NP; this coupling was abrogated in NP patients, in whom cognitive performance instead showed an opposite relationship with Complex V. Shared leading-edge genes defined a 13-gene monocyte anchor representing this cognition-associated NP phenotype. Higher anchor scores were associated with coordinated oxidative phosphorylation and cytotoxic programs across CD3⁺ T-cell subsets in individuals without NP, but not in NP participants. T-cell receptor stratified analyses showed that this altered relationship occurred in both expanded and unexpanded T-cell populations. FC correlations also supported reduced monocyte-to-lymphocyte mitochondrial coordination in NP. These exploratory findings identify a sleep and cognition-linked monocyte mitochondrial phenotype characterized by altered myeloid–lymphoid immune coordination in NP. Full article

(This article belongs to the Special Issue Immunity in Neurodegenerative Diseases: Systemic Immune Imbalance, Neuroinflammation, and Beyond—2nd Edition)

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14 pages, 4314 KB

Open AccessArticle

Divergent Immune and Endothelial Responses to Insulin Resistance in Women with Polycystic Ovary Syndrome

by Daniela Koleva-Tyutyundzhieva, Maria Ilieva-Gerova, Presiyana Nyagolova, Petya Konsulova, Ekaterina Babadzhanova, Aleksandar Georgiev, Devarshi Kansara, Tanya Deneva and Maria Orbetzova

Int. J. Mol. Sci. 2026, 27(16), 7473; https://doi.org/10.3390/ijms27167473 - 21 Aug 2026

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder frequently associated with insulin resistance (IR) and increased cardiovascular risk. Soluble CD40 ligand (sCD40L) and soluble E-selectin (sE-selectin) are circulating biomarkers reflecting immune activation and endothelial dysfunction, respectively. However, their differential associations with IR [...] Read more.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder frequently associated with insulin resistance (IR) and increased cardiovascular risk. Soluble CD40 ligand (sCD40L) and soluble E-selectin (sE-selectin) are circulating biomarkers reflecting immune activation and endothelial dysfunction, respectively. However, their differential associations with IR in PCOS, particularly in the context of central obesity, remain incompletely understood. This cross-sectional study included 80 women with PCOS stratified according to waist-to-height ratio (WHtR > 0.50 vs. ≤0.50). Clinical, metabolic, hormonal, inflammatory, and endothelial parameters were evaluated. Correlation and multivariable regression analyses were performed to identify independent determinants of circulating sCD40L and sE-selectin. Women with central obesity exhibited significantly higher fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, systolic blood pressure (SBP), and sE-selectin concentrations, together with lower HDL cholesterol. No significant differences were observed in tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), or sCD40L. In adjusted regression models, fasting glucose independently predicted sCD40L (β = −0.27, 95% confidence interval (CI): −0.50 to −0.04, p = 0.020), whereas fasting insulin emerged as the strongest determinant of sE-selectin (β = 0.41, 95% CI: 0.17 to 0.65, p < 0.001). These findings suggest distinct associations of immune and endothelial biomarkers with IR in PCOS. Assessment of sCD40L and sE-selectin may provide complementary information for early cardiometabolic risk stratification in affected women. Full article

(This article belongs to the Special Issue Obesity: From Cellular Mechanism to Potential Molecular Therapies)

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2 pages, 1563 KB

Open AccessCorrection

Correction: Liu et al. CpLEA5, the Late Embryogenesis Abundant Protein Gene from Chimonanthus praecox, Possesses Low Temperature and Osmotic Resistances in Prokaryote and Eukaryotes. Int. J. Mol. Sci. 2015, 16, 26978–26990

by Yiling Liu, Lixia Xie, Xilong Liang and Shihong Zhang

Int. J. Mol. Sci. 2026, 27(16), 7472; https://doi.org/10.3390/ijms27167472 (registering DOI) - 21 Aug 2026

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Gene–Environment Interactions)

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16 pages, 1008 KB

Open AccessArticle

Comparative Effects of Sertraline, Methotrexate, and Biologic Therapies on Circulating Inflammatory and Neurotrophic Mediators and Striatal Gene Expression in Collagen-Induced Arthritis

by Grzegorz Chmielewski, Mateusz Mikiewicz, Jakub Kuna, Łukasz Jaśkiewicz, Joanna Czerwińska, Małgorzata Wróbel, Edyta Kaczorek-Łukowska, Michał S. Majewski and Magdalena Krajewska-Włodarczyk

Int. J. Mol. Sci. 2026, 27(16), 7471; https://doi.org/10.3390/ijms27167471 - 21 Aug 2026

Abstract

Rheumatoid arthritis is often accompanied by neuropsychiatric manifestations, suggesting interactions between systemic inflammation and the central nervous system. This study evaluated the effects of sertraline, compared with methotrexate, infliximab, and tocilizumab, on circulating inflammatory and neurotrophic mediators and the striatal expression of selected [...] Read more.

Rheumatoid arthritis is often accompanied by neuropsychiatric manifestations, suggesting interactions between systemic inflammation and the central nervous system. This study evaluated the effects of sertraline, compared with methotrexate, infliximab, and tocilizumab, on circulating inflammatory and neurotrophic mediators and the striatal expression of selected CNS-related genes in collagen-induced arthritis. Male Wistar rats were assigned to seven groups: adjuvant control, untreated arthritis, methotrexate, sertraline, methotrexate plus sertraline, infliximab, or tocilizumab. At week 12, circulating IL-6, IL-15, IL-10, BDNF, myostatin, and irisin were measured, and striatal BDNF, IL-1β, and GFAP expression was assessed by quantitative real-time PCR. IL-6 concentrations differed between groups, with the lowest values after infliximab treatment and the highest in untreated arthritic rats and animals receiving methotrexate plus sertraline or tocilizumab. IL-15 was highest in untreated arthritis, whereas IL-10 was generally higher in treated groups and peaked after tocilizumab. The IL-6/IL-10 ratio was lower in all treated groups than in untreated arthritis, with the most pronounced reduction observed after infliximab. Circulating BDNF concentrations were highest in the infliximab- and tocilizumab-treated groups. Striatal BDNF expression differed significantly between groups, whereas no significant between-group differences were detected in striatal GFAP or IL-1β expression. No significant between-group differences were observed for circulating myostatin or irisin. Sertraline-containing regimens were associated with lower IL-6/IL-10 ratios than untreated arthritis, whereas infliximab and tocilizumab were associated with the most pronounced changes in systemic inflammatory and neurotrophic parameters. Full article

(This article belongs to the Special Issue Latest Advances in Autoimmune and Inflammatory Rheumatic Diseases)

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19 pages, 4593 KB

Open AccessArticle

Multi-Omics Analysis of PBMCs Revealed Distinct Biological Differences Between Hemodialysis and Peritoneal Dialysis

by Maurizio Bruschi, Simona Granata, Silvia Lai, Valentina Pistolesi, Laura Barberio, Rossana D’Agostino, Francesca Sorace, Francesca Giordano, Paola Pontrelli, Loreto Gesualdo, Lida Tartaglione, Giovanni Candiano, Sonia Spinelli, Andrea Petretto, Chiara Lavarello, Edoardo La Porta, Michele Provenzano and Gianluigi Zaza

Int. J. Mol. Sci. 2026, 27(16), 7470; https://doi.org/10.3390/ijms27167470 - 20 Aug 2026

Abstract

Although the clinical differences between hemodialysis (HD) and peritoneal dialysis (PD) are well established, the specific biological mechanisms underlying these differences remain incompletely understood. We performed untargeted proteomic and transcriptomic analyses of peripheral blood mononuclear cells (PBMCs) from healthy controls (CTRs) and patients [...] Read more.

Although the clinical differences between hemodialysis (HD) and peritoneal dialysis (PD) are well established, the specific biological mechanisms underlying these differences remain incompletely understood. We performed untargeted proteomic and transcriptomic analyses of peripheral blood mononuclear cells (PBMCs) from healthy controls (CTRs) and patients with chronic kidney disease undergoing HD or PD. Key findings were validated in an independent cohort using standardized biomolecular techniques. Bioinformatic analysis identified 36 differentially expressed proteins and 19 transcripts between HD and PD according to the predefined FDR-adjusted significance threshold. Functional enrichment analysis revealed that these factors were primarily involved in cellular senescence, aging, and stress-response pathways. Among the identified molecules, interferon regulatory factor 8 (IRF8) was the only factor consistently upregulated in HD compared with PD in both omics analyses. This finding was confirmed by ELISA in an independent cohort (p < 0.0001). Kinase enrichment analysis prioritized Checkpoint Kinase 2 (CHEK2), which was also identified by proteomics, as a predicted upstream regulator and warrants further investigation. Overall, these findings identify distinct molecular signatures in PBMCs from HD and PD patients and suggest a potential association between HD and increased PBMC IRF8 abundance and a senescence-related signature, which requires validation in larger and longitudinal cohorts. Full article

(This article belongs to the Special Issue Bridging Molecular and Translational Research in Chronic Kidney Disease and Dysmetabolism)

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24 pages, 10366 KB

Open AccessArticle

Comparative Transcriptomic Analysis of Water-Deficit Responses in Japonica Hybrid Rice ‘Dianheyou 615′

by Xiaoli Zhou, Cui Zhang, Junjie Li, Xianyu Wang, Chunli Wang, Fan Luo, Wenfeng Zhang, Changhe Wei, Qian Zhu and Lijuan Chen

Int. J. Mol. Sci. 2026, 27(16), 7469; https://doi.org/10.3390/ijms27167469 - 20 Aug 2026

Abstract

Water deficit severely limits rice productivity. The elite Dian (D1)-type hybrid japonica rice ‘Dianheyou 615 (ZH1)’ exhibits exceptional drought adaptation in high-altitude rainfed uplands of the Yungui Plateau, yet the underlying molecular mechanisms remain unknown. We compared phenotypic and transcriptomic responses of ZH1 [...] Read more.

Water deficit severely limits rice productivity. The elite Dian (D1)-type hybrid japonica rice ‘Dianheyou 615 (ZH1)’ exhibits exceptional drought adaptation in high-altitude rainfed uplands of the Yungui Plateau, yet the underlying molecular mechanisms remain unknown. We compared phenotypic and transcriptomic responses of ZH1 and six other japonica cultivars under well-watered and water-deficit conditions. Water-deficit stress significantly impaired agronomic traits across all cultivars; however, ZH1 uniquely maintained relatively stable flag leaf morphology and seed-setting rate, and displayed distinctive stomatal traits, in stark contrast to its parental lines and other cultivars. Transcriptomic profiling at the jointing-to-booting stage defined a core drought response module of 174 conserved genes across all cultivars. Critically, by intersecting 1097 ZH1-specific genes with drought-responsive elements, we pinpointed 15 core, cultivar-specific regulatory genes. These candidates are enriched in functions related to cuticle formation, carbohydrate metabolism, and stress signaling; among them, a DREB transcription factor (LOC4347618) is a prime candidate. qRT-PCR validated their expression. Using CRISPR/Cas9-mediated gene editing, we generated homozygous knockout mutants for LOC4333842, LOC4347618, and LOC4328441. Under 20% PEG-6000-simulated drought stress, all three mutant lines showed significantly increased drought susceptibility relative to wild-type controls, confirming the positive regulatory roles of these genes in drought stress tolerance in japonica rice. These results establish these three genes as promising targets for molecular breeding aimed at enhancing drought resistance in rice. Full article

(This article belongs to the Special Issue Advance in Plant Abiotic Stress: 4th Edition)

28 pages, 7137 KB

Open AccessArticle

Quantum Chemical Tailoring of Donor–Acceptor Organic Nanomedicines for Nonlinear Optical Performance and Theragnostic Applications: Molecular Descriptors, In Silico, and Ab Initio Investigations

by Sehar Nadeem, Muhammad Usman Khan, Łukasz Szeleszczuk, Dariusz Maciej Pisklak, Marcin Gackowski, Salah Knani and Nadia Ayari

Int. J. Mol. Sci. 2026, 27(16), 7468; https://doi.org/10.3390/ijms27167468 - 20 Aug 2026

Abstract

Nonlinear optical (NLO) active chromophores and their applications in photothermal therapy (PTT) demonstrate great potential in modern theragnostics, owing to their efficient light–matter interactions. A recognized D–π–A chromophore, FTC-3f, which is reported to exhibit a high photothermal conversion efficiency (~51.11%), was structurally modified [...] Read more.

Nonlinear optical (NLO) active chromophores and their applications in photothermal therapy (PTT) demonstrate great potential in modern theragnostics, owing to their efficient light–matter interactions. A recognized D–π–A chromophore, FTC-3f, which is reported to exhibit a high photothermal conversion efficiency (~51.11%), was structurally modified with various spacers and acceptors to elucidate enhanced PTT and NLO behavior through DFT and TD-DFT simulations. Molecular geometries were optimized at the B3LYP/6-31G (d, p) level. Their electronic properties, charge separation, and efficient transition pathways were analyzed using frontier molecular orbitals (FMOs), density of states (DOS), UV–visible spectroscopy, photon-induced electron transfer (PET), and transition density matrix (TDM) analysis. Among all the derivatives, D4 exhibited the smallest HOMO–LUMO energy gap (1.701 eV). The highest first-order hyperpolarizability (β) values are found for D4 (1.50 × 10⁵ in the gas phase, 7.40 × 10⁵ in water, 3.06 × 10⁵ in benzene solvent). The β_HRS is found to be in the range 5.11 × 10⁴ to 2.97 × 10⁴ and DR (3.65 × 10⁵ to 4.53 × 10⁴) supports the strong NLO response and strong synergistic donor–acceptor interactions. The designed chromophores exhibit much higher SHG and EOPE responses at 532, 1907.21, and 1064 nm than FTC-3F, indicating great potential for the synthesis of effective NLO nanomedicine. Molecular docking with bovine serum albumin (PDB ID: 4F5S) and Bcl-2 (PDB ID: 2W3L) suggested favorable binding conformations, consistent with a potential for transport and apoptotic-targeting behavior. All 3D molecular descriptor parameters indicate that the designed chromophores have potential for preferential targeting in PTT. This study investigates how structural modifications of donor–π–acceptor chromophores influence their electronic, optical, nonlinear optical, and theragnostic properties, providing insights into molecular design strategies for advanced NLO-based nanomedicine applications. Full article

(This article belongs to the Special Issue Computer-Aided Drug Discovery: Insights from Computational Chemistry and Cheminformatics)

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26 pages, 20833 KB

Open AccessArticle

Non-Coding SNPs Regulate Bovine Muscle Satellite Cell Proliferation and Differentiation by Modulating PENK Expression

by Tianyi Wu, Feng Liu, Qunhao Niu, Zhida Zhao, Lupei Zhang, Huijiang Gao, Junya Li, Xue Gao and Lingyang Xu

Int. J. Mol. Sci. 2026, 27(16), 7467; https://doi.org/10.3390/ijms27167467 - 20 Aug 2026

Abstract

The functions of noncoding variants associated with complex traits in livestock remain poorly understood. In this study, we investigated two candidate noncoding variants within the XKR4-CHCHD7 locus identified from our previous analysis. Dual-luciferase reporter assays demonstrated allele-specific regulatory activity of these two regions [...] Read more.

The functions of noncoding variants associated with complex traits in livestock remain poorly understood. In this study, we investigated two candidate noncoding variants within the XKR4-CHCHD7 locus identified from our previous analysis. Dual-luciferase reporter assays demonstrated allele-specific regulatory activity of these two regions in bovine muscle satellite cells (BMSCs), 293T cells, and C2C12 cells. Endogenous deletion of the candidate regions using a clustered regularly interspaced short palindromic repeats (CRISPR)-based high-fidelity Cas12Max (hfCas12Max) system revealed that the region containing chr14:22840845 (SNP-0845) exerted broader effects on BMSC function including reduced proliferation and migration, altered cell-cycle progression, and enhanced myogenic differentiation. Expression screening of candidate effector genes further identified PENK and TMEM68 as downstream candidate genes for SNP-0845. Rescue experiments further showed that PENK exerted stronger recovery effects than TMEM68 on the proliferation and migration defects caused by deletion of this region, supporting PENK as a major candidate effector downstream of the SNP-0845. Functional assays showed that PENK knockdown impaired BMSC proliferation and migration while promoting myogenic differentiation, whereas PENK overexpression partially reversed these effects. In vivo Penk knockdown reduced quadriceps femoris weight and altered muscle fiber composition in mice. Collectively, our findings suggest that a noncoding regulatory region modulates BMSC fate and muscle growth-related processes through PENK. Full article

(This article belongs to the Section Molecular Biology)

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