International Journal of Molecular Sciences

20 pages, 510 KB

Open AccessReview

Tracking Active Fibroblast-Mediated Tissue Remodelling in Cardiomyopathies: Translational Insights from FAPI PET Imaging

by Inês Fortuna, Janete Santos, Paula Soeiro, Raquel Machado, Ana Oliveira, Jorge Pereira, Giuseppe Limongelli, Teresa Faria and Elisabete Martins

Int. J. Mol. Sci. 2026, 27(19), 8901; https://doi.org/10.3390/ijms27198901 (registering DOI) - 7 Oct 2026

Abstract

Myocardial fibrosis is a major pathological component of cardiac remodelling and contributes to ventricular stiffness, impaired myocardial function, heart failure progression, and arrhythmic vulnerability across a broad spectrum of cardiomyopathies. In hypertrophic cardiomyopathy (HCM), fibrotic remodelling encompasses both diffuse interstitial matrix expansion and [...] Read more.

Myocardial fibrosis is a major pathological component of cardiac remodelling and contributes to ventricular stiffness, impaired myocardial function, heart failure progression, and arrhythmic vulnerability across a broad spectrum of cardiomyopathies. In hypertrophic cardiomyopathy (HCM), fibrotic remodelling encompasses both diffuse interstitial matrix expansion and focal replacement fibrosis and is closely associated with disease severity and adverse clinical outcomes. Cardiac magnetic resonance (CMR), using late gadolinium enhancement (LGE) and quantitative parametric mapping, is central to non-invasive myocardial tissue characterization. LGE primarily identifies focal areas of replacement fibrosis and scar, whereas native T1, T2, and extracellular volume (ECV) mapping provide complementary information on diffuse myocardial and interstitial tissue abnormalities, including extracellular matrix expansion. However, these techniques characterize the structural and tissue-level consequences of myocardial injury and remodelling rather than directly visualizing the cellular processes underlying fibroblast activation. Fibroblast activation protein inhibitor positron emission tomography (FAPI PET) has emerged as a promising molecular imaging approach for assessing active fibroblast-mediated tissue remodelling. By targeting fibroblast activation protein (FAP), a cell-surface serine protease upregulated in activated fibroblasts and myofibroblasts. FAPI radiotracers may provide a molecular readout of accessible FAP expression that complements structural and tissue characterization by CMR. This review examines the cellular and molecular mechanisms underlying active myocardial remodelling, with particular emphasis on transforming growth factor-β1 (TGF-β1)/Smad signalling, fibroblast-to-myofibroblast transition, FAP expression, and extracellular matrix turnover. We critically evaluate the current clinical evidence for FAPI PET/CT and hybrid PET/CMR across cardiomyopathies, focusing on HCM while also considering ischemic, inflammatory, infiltrative, and other non-ischemic forms of cardiac remodelling. Particular attention is given to the relationship between myocardial FAPI uptake, CMR tissue characterization, ventricular function, circulating biomarkers, and calculated arrhythmic risk. Although initial studies support the complementary value of FAPI PET and CMR for characterizing active and established myocardial remodelling, the available evidence remains limited by small, predominantly single-centre cohorts, heterogeneous radiotracers and acquisition protocols, and the absence of validated quantitative thresholds or prospective outcome data. Larger longitudinal studies are required to determine whether FAPI PET can provide incremental prognostic information or serve as a reproducible imaging biomarker for disease progression and therapeutic response. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Imaging and Therapy)

16 pages, 2192 KB

Open AccessArticle

Prehabilitation as a Strategy to Modulate the Tumor Microenvironment in Pancreatic Cancer

by Sanjna Sandeep, Jason Schutt, Kelvin Allenson, Renee Stubbins, Junjun Zheng, Shu-Hsia Chen and Atiya Dhala

Int. J. Mol. Sci. 2026, 27(19), 8900; https://doi.org/10.3390/ijms27198900 (registering DOI) - 7 Oct 2026

Abstract

Multimodal prehabilitation aims to enhance resilience to cancer therapy through exercise, nutrition, and psychological optimization. While prehabilitation can improve physical condition and functional status, its biologic influence on the tumor microenvironment (TME) remains poorly characterized. In pancreatic ductal adenocarcinoma (PDAC), the TME is [...] Read more.

Multimodal prehabilitation aims to enhance resilience to cancer therapy through exercise, nutrition, and psychological optimization. While prehabilitation can improve physical condition and functional status, its biologic influence on the tumor microenvironment (TME) remains poorly characterized. In pancreatic ductal adenocarcinoma (PDAC), the TME is dominated by immunosuppressive and desmoplastic features that limit immune cell infiltration and therapeutic efficacy. As an exploratory pilot analysis, this study characterized the cellular composition, spatial relationships, and functional signaling of the pancreatic TME in patients who underwent prehabilitation prior to surgical resection and those who did not. Tumor samples from eight patients (four prehabilitation, four control) were analyzed with a 34-plex protein panel using Imaging Mass Cytometry (IMC), categorizing the tumor–immune landscape and functional status at the single-cell resolution. Prehabilitation tumors demonstrated reduced neutrophil and epithelial/tumor cell density and enrichment of Natural Killer (NK), CD4⁺, and CD8⁺ T cells. Spatial analysis revealed an immune-permissive architecture in prehabilitation tumors, in contrast to immune-resistant patterns in controls. Functional marker analysis showed reduced activation and pro-tumor signaling in immunosuppressive populations, including Tregs (HLADR, pAkt, pNFκB) and Collagen⁺ CAFs (NOS2, pERK, pNFκB, pSTAT3). These preliminary findings raise the possibility that prehabilitation is associated with an immune-permissive TME in PDAC, supporting further investigation of its immunomodulatory potential in larger, prospectively designed cohorts. Full article

(This article belongs to the Section Molecular Oncology)

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18 pages, 7709 KB

Open AccessArticle

Progesterone Modulates Protein Synthesis in Osteoarthritic Fibroblast-like Synoviocytes

by Fadi Askar, Georgios Chatziagorou, Sofia Wüstenhagen, Alessia Capraro, Björn Andersson, Evelin Berger, Daniela Esposito, Luminita Labusca and Carmen Corciulo

Int. J. Mol. Sci. 2026, 27(19), 8899; https://doi.org/10.3390/ijms27198899 (registering DOI) - 7 Oct 2026

Abstract

Knee osteoarthritis (OA) is highly prevalent in women and is characterized by structural joint alterations and synovial inflammatory processes that contribute to pain and impaired mobility. In a previous study, we identified a positive correlation between progesterone levels and pain intensity in postmenopausal [...] Read more.

Knee osteoarthritis (OA) is highly prevalent in women and is characterized by structural joint alterations and synovial inflammatory processes that contribute to pain and impaired mobility. In a previous study, we identified a positive correlation between progesterone levels and pain intensity in postmenopausal women. However, the role of progesterone in synovial inflammation remains poorly understood. Therefore, this study aimed to characterize sex-specific differences in synovial tissue between postmenopausal women and age-matched men and to investigate the association between progesterone levels and the identified molecular profile. Whole blood and synovial tissue were collected from women and men with knee OA to assess plasma progesterone concentrations and the proteomic profiles of synovial tissue and isolated primary fibroblast-like synoviocytes (FLSs). The expression and localization of progesterone receptors were evaluated using RNAscope and immunofluorescence. FLS stimulated with physiological concentrations of progesterone were used for de novo protein synthesis assays. Quantitative proteomics of synovial tissue revealed enrichment of protein synthesis-related pathways in women compared to age-matched men, and isolated FLS from women with knee OA exhibited a pro-inflammatory and pro-fibrotic proteomic profile. Stratification by plasma progesterone levels identified two distinct patient groups, where lower progesterone levels were associated with pro-inflammatory signatures. The RNAscope analysis demonstrated increased transcriptional activity in synovial tissue from women with knee OA, localized to CD90⁺ sublining FLS. However, progesterone receptor expression at both the RNA and protein levels showed no sex-specific differences. Moreover, physiological concentrations of progesterone inhibited de novo protein synthesis in FLS isolated from men with knee OA. These findings underscore the hormonal context-dependent modulatory effects of progesterone on synovial inflammation and fibroblast activity. The study further highlights the importance of incorporating sex-specific hormonal profiles into OA patient stratification to support more precise and targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Highlights in Pathophysiology and Treatment of Osteoarthritis)

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17 pages, 652 KB

Open AccessArticle

Complementary Molecular and Spectroscopic Approaches for Meat Authentication: Real-Time PCR Detection of Porcine DNA and FT-NIR Analysis of Slaughter-Related Biochemical Changes

by Diyas Myrzakozha, Elmira Karlova, Saule Meldebekova, Tolkyn Issabekova, Nurgali Rakhymbayev, Nyshanbay Konash and Aliya Yermekkyzy

Int. J. Mol. Sci. 2026, 27(19), 8898; https://doi.org/10.3390/ijms27198898 (registering DOI) - 7 Oct 2026

Abstract

Food adulteration and species mislabeling represent important challenges for food safety, regulatory control, and consumer protection, particularly for products requiring species-specific authentication. This study investigated two complementary analytical approaches relevant to meat authentication: species-specific real-time polymerase chain reaction (real-time PCR) for the molecular [...] Read more.

Food adulteration and species mislabeling represent important challenges for food safety, regulatory control, and consumer protection, particularly for products requiring species-specific authentication. This study investigated two complementary analytical approaches relevant to meat authentication: species-specific real-time polymerase chain reaction (real-time PCR) for the molecular detection of porcine mitochondrial deoxyribonucleic acid (DNA) and Fourier-transform near-infrared (FT-NIR) spectroscopy combined with chemometric analysis for exploratory assessment of slaughter-related compositional changes in a controlled murine proof-of-concept model. A total of 85 commercially available Halal-labeled meat products, including sausages, cutlets, minced meat, dumplings, raw meat, and seasoning products, were analyzed for the presence of porcine mitochondrial DNA. Under the applied qualitative assay conditions, porcine mitochondrial DNA was detected in 64 of 85 analyzed samples (75.3%). This finding is specific to the investigated sample set and does not distinguish intentional formulation or substitution from unintended cross-contact or other potential sources of porcine-derived DNA. In parallel, FT-NIR spectroscopy over the 10,000–4000 cm⁻¹ spectral range was evaluated as a rapid, non-destructive approach for assessing compositional changes associated with blood removal in a controlled murine model. Principal component analysis of standard normal variate (SNV)-preprocessed spectra demonstrated separation between blood-retained and blood-drained tissues; the first principal component (PC1) and the second principal component (PC2) accounted for 93% and 4% of the total spectral variance, respectively. The spectral regions contributing most strongly to the observed separation were associated predominantly with O–H- and N–H- related vibrational features, consistent with variation in major tissue constituents such as water and proteins. These findings illustrate the complementary information provided by species-specific molecular detection and exploratory spectroscopic profiling. Further validation in commercially relevant livestock species and independent sample sets is required before a combined analytical workflow can be established. Full article

(This article belongs to the Special Issue From Biomolecules to Bioprocesses: Biochemical and Biotechnological Advances in Agri-Food Systems)

26 pages, 620 KB

Open AccessReview

Multiomics Insights in Research of Nitric Oxide (NO) Donors in Plants upon Stress

by Anastasia Gurina, Anna Margarit, Anastasia Zhikhreva, Nadezhda Frolova and Andrej Frolov

Int. J. Mol. Sci. 2026, 27(19), 8897; https://doi.org/10.3390/ijms27198897 - 7 Oct 2026

Abstract

It is known that the progressive climate changes and environmental pollution prevalent all over the world lead to increasingly frequent and prolonged episodes of stress, and it challenges plants to adapt to changing adverse conditions. Given the significant crop losses caused by challenging [...] Read more.

It is known that the progressive climate changes and environmental pollution prevalent all over the world lead to increasingly frequent and prolonged episodes of stress, and it challenges plants to adapt to changing adverse conditions. Given the significant crop losses caused by challenging environments, protecting plants from the destructive effects of these factors has become one of the most pressing challenges in modern agricultural biology and plant physiology. One of the approaches to protect plants from stressors in modern agrobiotechnology is the use of nitric oxide (NO) donors, which are chemicals that can release NO in plant cells and stimulate their germination, growth, biomass accumulation, and protection against external factors. Studying their mechanism of action at the molecular level is essential for understanding the targets of NO action, as well as for developing new phytoeffectors. A multiomics approach, along with physiological data, is often the method of choice. In this review, we compare widely used NO donors (e.g., sodium nitroprusside, S-nitrosoglutathione, NONOates) in terms of chemical properties, NO-release kinetics, stability, and suitability for different application methods (seed treatment, foliar spray, root application). Finally, we highlight recent advances from proteomics, metabolomics, and transcriptomics that have enabled system-wide identification of NO-responsive pathways and candidate targets. By integrating physiological, biochemical, and multiomics data, this review provides a framework for understanding NO-mediated stress tolerance and for the rational design of new NO-based phytoeffectors. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Plant Abiotic Stress Tolerance: 3rd Edition)

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17 pages, 6207 KB

Open AccessArticle

CFTR Functional Rescue and Heterogeneous Clinical Outcomes Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis Carrying the W1282R Variant

by Elena Kondratyeva, Anna Efremova, Yuliya Melyanovskaya, Elena Zhekaite, Maria Sapelnikova, Michael Milovanov, Olga Shchagina, Anna Voronkova, Victoria Sherman, Stanislav Krasovsky, Sergey Kutsev and Dmitry Goldshtein

Int. J. Mol. Sci. 2026, 27(19), 8896; https://doi.org/10.3390/ijms27198896 - 7 Oct 2026

Abstract

The clinical response to elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3–36 months in addition [...] Read more.

The clinical response to elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3–36 months in addition to ongoing standard CF therapy. Baseline lung function was generally preserved in patients with available spirometry (median percent predicted forced expiratory volume in 1 s (ppFEV₁), 110%; interquartile range (IQR), 93–123), limiting the potential for further improvement in ppFEV₁; no statistically significant change in ppFEV₁ was detected during ETI therapy (p = 0.328). Paired data for ppFEV₁, body mass index (BMI), and sweat conductivity were available for 8, 12, and 9 patients, respectively. CFTR function was assessed by intestinal current measurement (ICM; n = 4) and patient-derived intestinal organoids (n = 2). Functional testing demonstrated markedly reduced baseline CFTR activity. In the patient with paired ICM measurements before and during ETI therapy, restoration of CFTR-mediated chloride transport was observed, whereas ETI significantly increased forskolin-induced swelling (FIS) in both patient-derived organoid cultures (p < 0.001 for each culture). BMI did not change significantly during ETI therapy (p = 0.269). Sweat conductivity showed a statistically significant overall reduction (median change, −3 mmol/L; p = 0.031); however, marked reductions were observed in only two of nine patients. Interpretation is limited by the small retrospective cohort and incomplete availability of paired clinical and functional data. These findings indicate that functional responsiveness of W1282R-CFTR to ETI may not be accompanied by consistent improvement across the clinical outcomes assessed. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying the Pathogenesis of Genetic Diseases)

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18 pages, 2771 KB

Open AccessArticle

Proteomic and Molecular Biological Analyses of Response Mechanism in Rice (Oryza sativa L. cv. Koshihikari) Under Drought Stress

by Sheikh Shohag, Hisateru Yamaguchi, Keisuke Hitachi, Kunihiro Tsuchida and Setsuko Komatsu

Int. J. Mol. Sci. 2026, 27(19), 8895; https://doi.org/10.3390/ijms27198895 - 7 Oct 2026

Abstract

Drought stress severely limits rice growth, while roots play a key role in sensing water deficits and triggering adaptive responses. To investigate time-dependent molecular responses in rice (Oryza sativa L. cv. Koshihikari) under drought stress induced by polyethylene glycol (PEG), seedlings were [...] Read more.

Drought stress severely limits rice growth, while roots play a key role in sensing water deficits and triggering adaptive responses. To investigate time-dependent molecular responses in rice (Oryza sativa L. cv. Koshihikari) under drought stress induced by polyethylene glycol (PEG), seedlings were exposed to 10 and 20% PEG for 4 and 8 days, followed by morphological, proteomic, immunoblot, polymerase chain reaction, and ATP content analyses. Primary root length and total root fresh weight were significantly decreased with 20% PEG for 8 days compared with untreated. Proteomic analysis revealed changes in the abundance of rice root proteins under 20% PEG treatment between 4 and 8 days, with differentially abundant proteins enriched in Gene Ontology categories related to nuclear components, protein phosphorylation, and ATP binding. Selected proteins related to protein protection, redox-associated processes, and cytoskeletal responses were examined using immunoblot and polymerase chain reaction analyses. Glutathione S-transferase decreased and heat shock protein 70 increased with PEG for 8 days. The expression of NADPH-dependent codeinone reductase was upregulated and heat shock protein 17.9 was downregulated by PEG for 8 days. ATP content per unit fresh weight decreased in roots after PEG treatment. These results suggest that prolonged PEG-induced osmotic stress inhibits rice root growth through alterations in cellular energy status, the abundance of proteins involved in protein protection and glutathione S-transferase-mediated detoxification, and the expression of genes associated with reactive carbonyl species metabolism. Full article

(This article belongs to the Special Issue Advances in Plant Transporters and Tolerance Proteins)

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23 pages, 9679 KB

Open AccessArticle

Association of PTH1R Gene Polymorphisms with Three-Dimensional Mandibular Morphology Across Three Recruitment Cohorts

by Dongsan Shin, Ryosuke Kimura, Yong-Il Kim, Mohamed Adel, Seishiro Ueda, Masahiro Takahashi, Yu Hikita and Tetsutaro Yamaguchi

Int. J. Mol. Sci. 2026, 27(19), 8894; https://doi.org/10.3390/ijms27198894 - 7 Oct 2026

Abstract

Parathyroid hormone 1 receptor (PTH1R) regulates chondrocyte differentiation and mandibular condylar cartilage development, but its contribution to adult mandibular morphology remains unclear. We investigated associations of two PTH1R single-nucleotide polymorphisms (SNPs), rs724448 and rs2242116, with three-dimensional mandibular morphology in 448 orthodontic patients recruited [...] Read more.

Parathyroid hormone 1 receptor (PTH1R) regulates chondrocyte differentiation and mandibular condylar cartilage development, but its contribution to adult mandibular morphology remains unclear. We investigated associations of two PTH1R single-nucleotide polymorphisms (SNPs), rs724448 and rs2242116, with three-dimensional mandibular morphology in 448 orthodontic patients recruited in Japan (199), Korea (79), and Egypt (170). Salivary DNA was genotyped, and computed tomography images were analyzed using geometric morphometrics and conventional measurements. Multivariate Procrustes analysis evaluated overall mandibular shape. Cohort-specific regressions examined natural-log-transformed centroid size (ln(centroid size)), principal component scores, and conventional measurements, adjusting for sex and age and additionally for imaging modality in Japan. Estimates were combined using inverse-variance fixed-effect meta-analysis. Neither variant showed a significant whole-shape association after correction for two SNP tests. Secondary analyses yielded negative estimates for ln(centroid size) and nominal associations with selected anteroposterior dimensions and cohort-specific principal component scores. None remained significant after either Bonferroni or Benjamini–Hochberg false-discovery-rate correction across 408 tests. These findings provide no statistically robust evidence linking either variant to adult mandibular morphology. Nominal findings require independent replication. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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18 pages, 7115 KB

Open AccessArticle

microRNA and Regulatory Networks of Human Macrophage During Leishmania major In Vitro Infection

by Sara Habouria, Aymen Bali, Aurora Diotallevi, Ali Ben-Cheikh, Chiraz Atri, Mauro De Santi, Sara Maestrini, Luca Galluzzi, Dhafer Laouini and Fatma Zahra Guerfali

Int. J. Mol. Sci. 2026, 27(19), 8893; https://doi.org/10.3390/ijms27198893 - 7 Oct 2026

Abstract

Leishmania (L.) major modulates host microRNA (miR) expression to promote intracellular survival, yet the roles of specific miRs during early infection of human macrophages remain poorly defined. We investigated the dynamic regulation of miR-21-5p and miR-146a-5p in THP-1-derived macrophages infected with [...] Read more.

Leishmania (L.) major modulates host microRNA (miR) expression to promote intracellular survival, yet the roles of specific miRs during early infection of human macrophages remain poorly defined. We investigated the dynamic regulation of miR-21-5p and miR-146a-5p in THP-1-derived macrophages infected with L. major over an early post-infection time course (3–48 h), alongside miR-30a-3p and miR-101-3p. Both miR-21-5p and miR-146a-5p were significantly upregulated during the early stages of infection (3–24 h) before declining by 48 h. Using antisense LNA inhibitors, we achieved independent single and dual silencing of both miRs, allowing us to dissect their functional contribution to host gene expression. In silico network analysis identified 887 shared and specific target genes, including NFKB1, MYC, STAT3, HIF1A, TNF, CXCL8, IL18, and XBP1. Silencing of miR-21-5p and miR-146a-5p at early time points relieved inhibitory control over several of these targets, notably increasing NF-κB, MYC, IL18 and XBP1 expression, and reducing TNF and sXBP1, consistent with their role as negative regulators of innate immune signaling. These findings identify miR-21-5p and miR-146a-5p as early, dynamic regulators of the human macrophage transcriptional response to L. major infection and identify their target genes as candidate biomarkers and therapeutic targets in cutaneous leishmaniasis. Full article

(This article belongs to the Special Issue Molecular Advances in Zoonoses and Vector-Borne Diseases)

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23 pages, 9994 KB

Open AccessArticle

Integrative Phosphoproteomic Characterization of ULK1 Phosphosites Reveals Co-Regulatory Networks in Autophagy and Metabolic Adaptation

by Furqaan Ahmed Basha, Sreeshma Ravindran Kammarambath, Leona Dcunha, Althaf Mahin, Athira Perunelly Gopalakrishnan, Alimath Sambreena, Inamul Hasan Madar and Rajesh Raju

Int. J. Mol. Sci. 2026, 27(19), 8892; https://doi.org/10.3390/ijms27198892 - 7 Oct 2026

Abstract

Unc-51-like autophagy-activating kinase 1 (ULK1), a serine/threonine kinase, is the central regulator of autophagy initiation and plays a crucial role in cellular homeostasis, metabolic adaptation, and stress responses. We performed a large-scale phosphoproteomic data analysis of ULK1 by systematically integrating and analyzing 891 [...] Read more.

Unc-51-like autophagy-activating kinase 1 (ULK1), a serine/threonine kinase, is the central regulator of autophagy initiation and plays a crucial role in cellular homeostasis, metabolic adaptation, and stress responses. We performed a large-scale phosphoproteomic data analysis of ULK1 by systematically integrating and analyzing 891 profiling and 245 differential human phosphoproteomic datasets. S450, S623, and S638 emerged as the predominant phosphosites in ULK1, with the highest frequency of detection across multiple cellular phosphoproteomics datasets. Conservation analysis showed that these phosphosites are conserved across mammalian species and human ULK1 and ULK2 (Unc-51-like autophagy-activating kinase 2). The co-regulatory networks associated with these phosphosites, including interacting proteins, upstream kinases, and downstream substrates, were systematically analyzed. The phosphosite co-regulated ULK1 interactome revealed a network of associations linking ubiquitin-dependent cargo recognition to autophagosome biogenesis, trafficking, and maturation, indicating that ULK1 phosphoregulation may extend beyond its established role in autophagy initiation and be associated with multiple stages of selective autophagy. Notably, ULK1 phosphosites were linked to key metabolic enzymes in glycogen, sphingolipid, phospholipid, and glycolytic pathways, as well as classical lipolysis. Protein-normalized analysis across 12 cancer cohorts showed significant upregulation of the predominant ULK1 phosphosites, most frequently at S450 and S623. Comparative analysis with an independent ULK1/2 knockout phosphoproteomic dataset further supported the relevance of these identified co-regulated protein phosphosites. Collectively, this study provides a phosphosite-resolved view of ULK1 regulation and identifies candidate phosphosites and associated proteins for future functional and mechanistic studies. Full article

(This article belongs to the Special Issue Advances in Mass Spectrometry-Based Proteomics: From Biomarker Discovery to Translational Applications)

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24 pages, 2101 KB

Open AccessArticle

Meta-Inflammation in Type 2 Diabetes Mellitus: Theoretical, Methodological, and Clinical Aspects

by Yulia Zhuravleva and Evgenii Gusev

Int. J. Mol. Sci. 2026, 27(19), 8891; https://doi.org/10.3390/ijms27198891 - 7 Oct 2026

Abstract

Currently, there is no doubt that insulin resistance (IR) in prediabetes and type 2 diabetes mellitus (T2DM) is associated with chronic systemic metabolic inflammation (SMI). SMI is typically considered a form of low-grade systemic inflammation (LGSI). At the same time, one cannot rule [...] Read more.

Currently, there is no doubt that insulin resistance (IR) in prediabetes and type 2 diabetes mellitus (T2DM) is associated with chronic systemic metabolic inflammation (SMI). SMI is typically considered a form of low-grade systemic inflammation (LGSI). At the same time, one cannot rule out the possibility of the transformation of LGSI into more pronounced forms of chronic systemic inflammation (ChSI), typical of systemic autoimmune diseases and characterized by a high severity of systemic inflammatory response (SIR). The aim of this research is to assess the pathogenetic role of SMI as a general pathological process in the pathogenesis of prediabetes and T2DM, as well as differentiating SMI into LGSI and ChSI. The study included two main groups—T2DM (n = 65) and prediabetes (n = 24)—as well as three control groups of healthy individuals of different ages (n = 50, n = 89, and n = 22). In the patients of the main groups, metabolic syndrome (MetS) was diagnosed in accordance with the American Heart Association criteria, and metabolic indices (HOMA-IR, HOMA-islet, and TyG) were calculated. The levels of C-reactive protein (CRP) and cytokines (TNFα, IL-6, IL-8, and IL-10) were determined in blood plasma as SIR parameters, and the levels of cortisol (690 nmol/L or <100 nmol/L), D-dimer (>250 and >500 ng/mL), and troponin I (>0.2 ng/mL) were used as additional SMI criteria. Based on molecular inflammatory markers, the ChSI and LGSI scales were calculated using the authors’ original method. SMI in T2DM and prediabetes manifested itself as both LGSI (in 57% of cases in T2DM and 46% in prediabetes) and ChSI (in 18.5% of cases in T2DM and 8.3% in prediabetes). The verification of SMI based on the frequently used criterion of CRP levels above 3 mg/L turned out to be ineffective in our study (this criterion was detected in the control groups in 24–45%). Therefore, we used CRP > 10 mg/L in combination with cytokines as the SIR criterion. Additionally, we identified the SMI criteria: D-dimer > 250 ng/mL in 27.7% of T2DM and 0% in the control groups and prediabetes; cortisol 15.4% in T2DM and 8.3% in prediabetes; and troponin I 7.7% in T2DM and 4.2% in prediabetes. SMI (LGSI and ChSI) develops in the majority of patients with prediabetes (54.1%) and T2DM (75.4%). To assess SMI, it is advisable to use the integral SIR criteria in combination with the markers of chronic stress, tissue damage, and coagulopathy. Full article

(This article belongs to the Special Issue Metabolic Inflammation and Adipose Tissue)

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21 pages, 5334 KB

Open AccessReview

A Proposed Convergent Genetic and Molecular Framework for Legg–Calvé–Perthes Disease: A Scoping Review

by Edgar Hernández-Zamora, Armando Odiseo Rodríguez-Olivas, Marlene Alejandra Galicia-Alvarado, Leonora Casas-Ávila and Elba Reyes-Maldonado

Int. J. Mol. Sci. 2026, 27(19), 8890; https://doi.org/10.3390/ijms27198890 - 7 Oct 2026

Abstract

Legg–Calvé–Perthes disease (LCPD) is a rare pediatric disorder characterized by avascular osteonecrosis of the femoral head. Its pathogenesis is multifactorial, and genetic, epigenetic, vascular, and inflammatory mechanisms may contribute to disease susceptibility and progression. To map and characterize the available evidence on genetic [...] Read more.

Legg–Calvé–Perthes disease (LCPD) is a rare pediatric disorder characterized by avascular osteonecrosis of the femoral head. Its pathogenesis is multifactorial, and genetic, epigenetic, vascular, and inflammatory mechanisms may contribute to disease susceptibility and progression. To map and characterize the available evidence on genetic and epigenetic factors and molecular pathways associated with LCPD, with particular emphasis on potential interactions and convergence across biological pathways. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR, PRISMA 2020 for Abstracts checklist). PubMed/MEDLINE was searched for studies published between March 2006 and March 2026. Relevant genetic, epigenetic, and molecular findings were extracted and synthesized according to biological pathways. See the PRISMA 2020 for Abstracts checklist. Seventeen genes and 25 single-nucleotide variants (SNVs), as reported in the included literature, were identified and grouped into three major biological axes: hypercoagulability, inflammation, and bone metabolism and remodeling. Associations with LCPD were reported in at least one study for F5 rs6025, MTHFR rs1801133, IL6 rs1800795, IL23R rs1569922, NOS3 rs1799983 and rs2070744, and OPG rs2073618. Epigenetic mechanisms, including DNA methylation and microRNA dysregulation, were also reported. Interpretation was limited by methodological heterogeneity, small study populations, limited functional validation, and a predominance of observational studies. Accumulating evidence suggests that thrombotic, inflammatory, bone remodeling, and epigenetic mechanisms contribute to LCPD susceptibility and pathogenesis. Our findings point to a potential biological convergence among these pathways; however, whether this convergence stems from a shared genetic architecture remains to be fully elucidated. LCPD pathogenesis involves a complex interplay of coagulation, inflammation, bone remodeling, and epigenetic pathways. While these mechanisms suggest biological convergence, their precise shared genetic architecture remains uncertain. Consequently, future studies utilizing independent replication and functional validation are critically needed. Full article

(This article belongs to the Section Molecular Biology)

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22 pages, 4650 KB

Open AccessArticle

Biopriming of Durum Wheat Seeds with Diazotrophic Bacteria Improved Physiological and Biochemical Pathways Under Salt Stress

by Adel Hadj Brahim, Zouhour Said, Eya Frikha, Mouna Jlidi, Manel Ben Ali and Mamdouh Ben Ali

Int. J. Mol. Sci. 2026, 27(19), 8889; https://doi.org/10.3390/ijms27198889 - 7 Oct 2026

Abstract

A significant strategy for sustainable management, by decreasing the use of chemical fertilizers, can consist of technology based on suitable levels of plant growth promoting bacteria (PGPB) seed biopriming. The main goal of this work was to demonstrate the positive effect of PGPB [...] Read more.

A significant strategy for sustainable management, by decreasing the use of chemical fertilizers, can consist of technology based on suitable levels of plant growth promoting bacteria (PGPB) seed biopriming. The main goal of this work was to demonstrate the positive effect of PGPB as seed biopriming factor on the growth of durum wheat plantlets under stress. plantlets physiological and biochemical pathways modifications were assessed in controlled growth chamber under salt stress. Seeds bioprimed with bacterial strains, in particular, Bacillus pumilus (MA9), Virgibacillus halodenitrificans (MA14), Bacillus subtilis (MA17), and Bacillus pumilus (MA19), demonstrated the best development of durum wheat seedlings under salt stress. The total length and total dry weight were altogether higher in bioprimed than in unbioprimed plants. The PGPB-bioprimed plants were very sound and hydrated, and the unbioprimed plant leaves were parched within 120 mM NaCl. In contrast to explants without PGPB, all the biochemical variables, for example, auxin, proline, soluble sugars, amino acids, and protein, were essentially improved in bioprimed explants. Biopriming with MA17 fundamentally diminished the reactive oxygen species (ROS) rate, particularly without salt stress. In any case, this impact of the hindrance of “ROS” was more pronounced under stressful conditions. The explant antioxidant prevention agent pathways catalase (CAT) and ascorbate peroxidase (APX) and the chlorophyll content were improved after seed biopriming with PGPB when explants with unbioprimed seeds had low cell reinforcement pathways under the two treatments, particularly under pressure. The bioprimed plants additionally had higher K⁺/Na⁺ proportions and expanded intracellular K⁺ ion activity. Hence, it can be anticipated that seed biopriming with PGPB is a novel technology that can improve healthy plant development under saline conditions. This study shows that PGPB has a significant effect in initiating resistance under stressful conditions in plants and can be utilized to develop new bioinoculants to reduce the use of chemical fertilizers. Full article

(This article belongs to the Special Issue Physiology and Molecular Biology of Plant Stress Tolerance: 3rd Edition)

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14 pages, 5056 KB

Open AccessReview

Low Nephron Number and Kidney Disease

by Samaneh Goorani and John D. Imig

Int. J. Mol. Sci. 2026, 27(19), 8888; https://doi.org/10.3390/ijms27198888 - 7 Oct 2026

Abstract

Reduced nephron endowment and acquired nephron loss increase susceptibility to hypertension and chronic kidney disease (CKD). Low birth weight, prematurity, genetic factors, and adverse prenatal exposures can limit nephron development, whereas aging and kidney injury reduce the number of functioning nephrons after birth. [...] Read more.

Reduced nephron endowment and acquired nephron loss increase susceptibility to hypertension and chronic kidney disease (CKD). Low birth weight, prematurity, genetic factors, and adverse prenatal exposures can limit nephron development, whereas aging and kidney injury reduce the number of functioning nephrons after birth. Compensatory glomerular hypertrophy and increased single-nephron filtration can initially preserve overall glomerular filtration rate, but sustained glomerular stress may promote podocyte injury, proteinuria, and glomerulosclerosis. These changes can accelerate nephron loss and create a cycle of progressive kidney damage. Disease susceptibility depends on genetic background and additional metabolic, environmental, and hemodynamic stresses. This review examines the determinants of nephron number, the adaptive and potentially harmful consequences of nephron reduction, and approaches to preserving kidney function. Improving maternal health, reducing harmful exposures, and controlling hypertension and metabolic disease may reduce the long-term consequences of low nephron number. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Mechanisms and Therapies)

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12 pages, 875 KB

Open AccessReview

Molecular Mechanisms Underlying Progression and Spontaneous Regression in Desmoid Tumors

by Shinji Miwa, Katsuhiro Hayashi, Takashi Higuchi, Hirotaka Yonezawa, Sei Morinaga, Yohei Asano and Satoru Demura

Int. J. Mol. Sci. 2026, 27(19), 8887; https://doi.org/10.3390/ijms27198887 - 7 Oct 2026

Abstract

Desmoid-type fibromatosis, also known as desmoid tumor (DT), is a rare and locally aggressive soft tissue neoplasm driven by constitutive activation of the Wnt/β-catenin signaling pathway, most commonly through CTNNB1 or APC alterations. While some tumors progress and cause substantial morbidity, approximately 25–38% [...] Read more.

Desmoid-type fibromatosis, also known as desmoid tumor (DT), is a rare and locally aggressive soft tissue neoplasm driven by constitutive activation of the Wnt/β-catenin signaling pathway, most commonly through CTNNB1 or APC alterations. While some tumors progress and cause substantial morbidity, approximately 25–38% undergo spontaneous regression during active surveillance, which is currently recommended as the first-line management strategy. Although advances in next-generation sequencing and transcriptomic profiling have elucidated the molecular drivers of tumor progression, the molecular mechanisms underlying spontaneous regression remain poorly understood. This review summarizes current knowledge of the molecular pathogenesis of DT and proposed mechanisms of spontaneous regression, including attenuation of Wnt/β-catenin signaling, hormonal modulation, alterations in the immune microenvironment, and crosstalk between Wnt signaling and other pathways such as Notch, PDGFR/c-Abl/HIF1α, and TGF-β. Based on the current knowledge of the molecular mechanisms in DT, spontaneous regression appears to reflect a multifactorial transition from an active proliferative state toward a quiescent, fibrotic phenotype rather than a single molecular event. Further studies integrating single-cell and spatial transcriptomics with immune profiling are warranted to identify therapeutic targets and stratify patients for active surveillance versus active treatment. Full article

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13 pages, 995 KB

Open AccessArticle

Simple Synthesis of Fused 1,3,4-Thiadiazines Through Successive S_NAr Processes

by Vladislav V. Nikol’skiy, Alexey M. Starosotnikov, Alexey K. Fedorenko, Ivan V. Fedyanin, Artem N. Fakhrutdinov and Maxim A. Bastrakov

Int. J. Mol. Sci. 2026, 27(19), 8886; https://doi.org/10.3390/ijms27198886 - 6 Oct 2026

Abstract

A convenient method is described for the synthesis of novel 2-arylazo-1,3,4-thiadiazines fused with pyridine, pyrimidine or pyrazole ring. The synthetic strategy relies on a one-pot tandem cascade that proceeds through three consecutive steps without the isolation of intermediates: (1) nucleophilic aromatic substitution (SNAr) [...] Read more.

A convenient method is described for the synthesis of novel 2-arylazo-1,3,4-thiadiazines fused with pyridine, pyrimidine or pyrazole ring. The synthetic strategy relies on a one-pot tandem cascade that proceeds through three consecutive steps without the isolation of intermediates: (1) nucleophilic aromatic substitution (SNAr) of the chlorine atom by the dithizone nucleophile, (2) intramolecular S-N-type Smiles rearrangement involving migration of the hetaryl fragment from nitrogen to sulfur, and (3) intramolecular nucleophilic substitution of the activated nitro group, which closes the fused thiadiazine ring. The use of ortho-chloronitro hetarenes is essential, as the nitro group serves both as an activating substituent for the initial SNAr step and as a leaving group in the final cyclization step. UV-Vis absorption spectra of the synthesized compounds were recorded. Full article

(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity—2nd Edition)

17 pages, 855 KB

Open AccessArticle

Serum BDNF, VEGF, and EGF Levels in Pregnant Women with Anxiety and Depression

by Philippe Leff-Gelman, Ismael Mancilla-Herrera, Amado Pérez-Molina, Mónica Flores-Ramos, Blanca Farfan-Labonne, Fausto Manuel Cruz-Coronel, María del Pilar Meza-Rodríguez, Ignacio Camacho-Arroyo and Carlos S. Cruz-Fuentes

Int. J. Mol. Sci. 2026, 27(19), 8885; https://doi.org/10.3390/ijms27198885 - 6 Oct 2026

Abstract

Antenatal anxiety and depression frequently co-occur, negatively affecting maternal and offspring outcomes, yet their biological correlates remain insufficiently characterized. This cross-sectional study examined associations between anxiety and depressive symptoms and serum concentrations of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and [...] Read more.

Antenatal anxiety and depression frequently co-occur, negatively affecting maternal and offspring outcomes, yet their biological correlates remain insufficiently characterized. This cross-sectional study examined associations between anxiety and depressive symptoms and serum concentrations of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), proteins implicated in pregnancy-related vascular adaptations whose dysregulation has been associated with placental dysfunction and negative perinatal outcomes. A total of 148 women with uncomplicated second- and third-trimester pregnancies were assessed using the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. Serum BDNF levels were quantified by enzyme-linked immunosorbent assay, whereas VEGF and EGF were measured using a multiplex bead-based immunoassay during late pregnancy. Based on scale scores, participants were classified as controls, women with anxiety without depressive symptoms, or women with anxiety and depressive symptoms. In the between-group comparisons, women with clinically significant anxiety exhibited higher BDNF and EGF levels than controls. Regression analyses indicated that anxiety severity was positively associated with BDNF, VEGF, and EGF levels (all p < 0.05), whereas depressive symptom severity was negatively associated with BDNF levels (p < 0.05). These findings suggest distinct associations of antenatal anxiety and depressive symptoms with circulating growth factors, particularly BDNF, and warrant further investigation of vascular–immune–neurotrophic pathways potentially involved in perinatal mental health. Full article

(This article belongs to the Special Issue Advances in Neuroscience of Mental Disorders: Neuropsychological, Neurobiological and Neuromolecular Perspectives)

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17 pages, 2084 KB

Open AccessBrief Report

Partial Expression of Genes and Some Proteins Associated with the Dopaminergic Phenotype in Vasopressinergic Neurons of the Supraoptic Nucleus in Intact Mice

by Tatiana S. Pronina, Dmitry V. Troshev, Liliya K. Dil’mukhametova, Maria O. Shchepina and Michael V. Ugrumov

Int. J. Mol. Sci. 2026, 27(19), 8884; https://doi.org/10.3390/ijms27198884 - 6 Oct 2026

Abstract

Nearly forty years ago, it was first discovered that vasopressinergic neurons in the supraoptic nucleus contain tyrosine hydroxylase (TH), the first enzyme of dopamine synthesis. In some mammals, it is expressed only under stress, such as osmotic stimulation and so on (rats); in [...] Read more.

Nearly forty years ago, it was first discovered that vasopressinergic neurons in the supraoptic nucleus contain tyrosine hydroxylase (TH), the first enzyme of dopamine synthesis. In some mammals, it is expressed only under stress, such as osmotic stimulation and so on (rats); in others it is expressed under normal conditions (tree shrews), and in a third group it is expressed in pathology (humans). This study is devoted to testing the hypothesis that vasopressinergic neurons may express some other proteins of the dopaminergic phenotype in addition to TH. To meet this aim, we assessed the expression of genes encoding proteins of the dopaminergic phenotype, such as TH, aromatic L-amino acid decarboxylase, vesicular monoamine transporter 2, and dopamine transporter, in vasopressin-immunopositive neurons of the supraoptic nucleus of intact C57BL/6 mice isolated by laser microdissection. We demonstrated that vasopressinergic neurons of the supraoptic nucleus express the genes for all of the aforementioned dopaminergic phenotype proteins, with the exception of the dopamine transporter. In a subsequent immunohistochemical study, evidence was obtained that, in addition to TH, some vasopressinergic neurons contain aromatic L-amino acid decarboxylase and, perhaps, vesicular monoamine transporter 2. Further studies are needed to determine whether the dopaminergic phenotype proteins we identified possess specific functional activity. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases, 2nd Edition)

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23 pages, 1891 KB

Open AccessReview

Sartans and Bisartans: Expanding Therapeutic Horizons Through Broad Receptor Interactions and Repurposing Potential

by Errikos Petsas, Vasso Apostolopoulos, Despoina P. Kiouri, Konstantinos Kelaidonis, Harry Ridgway, Graham J. Moore, Thomas Mavromoustakos, Laura Kate Gadanec, John M. Matsoukas and Christos T. Chasapis

Int. J. Mol. Sci. 2026, 27(19), 8883; https://doi.org/10.3390/ijms27198883 - 6 Oct 2026

Abstract

Angiotensin receptor blockers (ARBs), also known as sartans, are a family of highly selective angiotensin II type 1 receptor antagonists commonly prescribed to individuals with hypertension, heart failure, and chronic kidney disease. Additionally, the discovery and facile synthesis of bisartans, a novel class [...] Read more.

Angiotensin receptor blockers (ARBs), also known as sartans, are a family of highly selective angiotensin II type 1 receptor antagonists commonly prescribed to individuals with hypertension, heart failure, and chronic kidney disease. Additionally, the discovery and facile synthesis of bisartans, a novel class of ARB antihypertensives, have shown therapeutic promise for cardiovascular diseases. Recent computational and network pharmacology studies have shown a broader receptor interactome, encompassing alpha-adrenergic receptors, and delta- and mu-opioid receptors, highlighting the polypharmacology of ARBs. Herein, we combine molecular docking, molecular dynamics, and protein–protein interaction analyses to characterize the binding profiles of sartans and bisartans, as well as conformational impacts across multiple G-protein-coupled receptors. Emphasis is placed on their potential to modulate receptor desensitization states and influence pathways involved in neuropsychiatric disorders, addiction, viral infections, and cardiovascular diseases. Limitations of current computational approaches are discussed alongside the need for experimental proteomic validation. Collectively, this evidence positions sartans and bisartans as structurally privileged scaffolds for multi-target drug repurposing and precision medicine applications. Full article

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

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