International Journal of Molecular Sciences

17 pages, 2031 KB

Open AccessReview

Ambiguous Role of p53 in Transcription-Dependent Tumor Cell Death

by Angelina A. Romanova, Tatyana A. Grigoreva, Anastasia D. Zenina, Anna D. Smirnaya, Kira Y. Margolina, Aleksandra Sagaidak and Vyacheslav G. Tribulovich

Int. J. Mol. Sci. 2026, 27(2), 769; https://doi.org/10.3390/ijms27020769 (registering DOI) - 12 Jan 2026

Abstract

Currently, research in anti-cancer therapy remains a priority. This is driven by two main challenges: the difficulty of modeling and developing targeted or precision drugs and the multiple, often unpredictable, body responses to treatment. The primary objective of modern anti-cancer drugs is the [...] Read more.

Currently, research in anti-cancer therapy remains a priority. This is driven by two main challenges: the difficulty of modeling and developing targeted or precision drugs and the multiple, often unpredictable, body responses to treatment. The primary objective of modern anti-cancer drugs is the induction of cancer cell death. One of the key regulators of cell death is the tumor suppressor protein p53. This protein is a well-known transcription factor encoded by TP53. Despite the fact that p53 is generally considered a pro-apoptotic inducer, it also regulates cell death pathways such as necrosis and autophagy. Given the diversity of p53-mediated cell death pathways, establishing a specific activated mechanism is a necessary step in developing effective anti-cancer drugs, since certain types of cell death can cause adverse outcomes in patients, including infection, sepsis, tumor progression and metastasis. The review summarizes knowledge about p53-dependent cell death mechanisms and the p53 transcriptional targets that are involved. It also describes shared molecular pathways among apoptosis, necrosis, and autophagy, as well as the methods and markers used to distinguish one type of cell death from another. Full article

(This article belongs to the Special Issue Oncogenes and Tumor Suppressors: From Basic Science to Therapeutic Applications)

23 pages, 4621 KB

Open AccessArticle

Tuber Inoculation Drives Rhizosphere Microbiome Assembly and Metabolic Reprogramming in Corylus

by Jing Wang, Nian-Kai Zeng and Xueyan Zhang

Int. J. Mol. Sci. 2026, 27(2), 768; https://doi.org/10.3390/ijms27020768 (registering DOI) - 12 Jan 2026

Abstract

To elucidate the potential of integrated multi-omics approaches for studying systemic mechanisms of mycorrhizal fungi in mediating plant-microbe interactions, this study employed the Tuber-inoculated Corylus system as a model to demonstrate how high-throughput profiling can investigate how fungal inoculation reshapes the rhizosphere [...] Read more.

To elucidate the potential of integrated multi-omics approaches for studying systemic mechanisms of mycorrhizal fungi in mediating plant-microbe interactions, this study employed the Tuber-inoculated Corylus system as a model to demonstrate how high-throughput profiling can investigate how fungal inoculation reshapes the rhizosphere microbial community and correlates with host metabolism. A pot experiment was conducted comparing inoculated (CTG) and non-inoculated (CK) plants, followed by integrated multi-omics analysis involving high-throughput sequencing (16S/ITS), functional prediction (PICRUSt2/FUNGuild), and metabolomics (UPLC-MS/MS). The results demonstrated that inoculation significantly restructured the fungal community, establishing Tuber as a dominant symbiotic guild and effectively suppressing pathogenic fungi. Although bacterial alpha diversity remained stable, the functional profile shifted markedly toward symbiotic support, including antibiotic biosynthesis and environmental adaptation. Concurrently, root metabolic reprogramming occurred, characterized by upregulation of strigolactones and downregulation of gibberellin A5, suggesting a potential “symbiosis-priority” strategy wherein carbon allocation shifted from structural growth to energy storage, and plant defense transitioned from broad-spectrum resistance to targeted regulation. Multi-omics correlation analysis further revealed notable associations between microbial communities and root metabolites, proposing a model in which Tuber acts as a core regulator that collaborates with the host to assemble a complementary micro-ecosystem. In summary, the integrated approach successfully captured multi-level changes, suggesting that Tuber-Corylus symbiosis constitutes a fungus-driven process that transforms the rhizosphere from a competitive state into a mutualistic state, thereby illustrating the role of mycorrhizal fungi as “ecosystem engineers” and providing a methodological framework for green agriculture research. Full article

(This article belongs to the Section Molecular Microbiology)

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31 pages, 1759 KB

Open AccessReview

Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling

by Ioan Tilea, Dragos-Gabriel Iancu, Ovidiu Fira-Mladinescu, Nicoleta Bertici and Andreea Varga

Int. J. Mol. Sci. 2026, 27(2), 767; https://doi.org/10.3390/ijms27020767 (registering DOI) - 12 Jan 2026

Abstract

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a [...] Read more.

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

(This article belongs to the Section Molecular Pharmacology)

20 pages, 2963 KB

Open AccessArticle

A Distinct Defense Strategy: The Molecular Basis of WSSV Tolerance in Macrobrachium nipponense Revealed by Comparative Transcriptomics with Litopenaeus vannamei

by Yunpeng Niu, Sufei Jiang, Wenyi Zhang, Yiwei Xiong, Shubo Jin, Hui Qiao and Hongtuo Fu

Int. J. Mol. Sci. 2026, 27(2), 766; https://doi.org/10.3390/ijms27020766 (registering DOI) - 12 Jan 2026

Abstract

White Spot Syndrome Virus (WSSV) remains one of the most devastating pathogens in global shrimp aquaculture, causing massive economic losses annually. This study employed comparative transcriptomics to elucidate the molecular basis of the differential resistance to WSSV between the highly susceptible Pacific white [...] Read more.

White Spot Syndrome Virus (WSSV) remains one of the most devastating pathogens in global shrimp aquaculture, causing massive economic losses annually. This study employed comparative transcriptomics to elucidate the molecular basis of the differential resistance to WSSV between the highly susceptible Pacific white shrimp (Litopenaeus vannamei) and the remarkably resistant oriental river prawn (Macrobrachium nipponense). Our analysis of gill, hepatopancreas, and muscle tissues at 24 h post-infection revealed fundamentally distinct defense strategies. The resistant M. nipponense employs a unique “proactive homeostatic reinforcement” strategy, characterized by significant enrichment of pathways central to cellular homeostasis, including signal transduction, cellular processes, and transport/catabolism. This approach, supported by coordinated up-regulation of heat shock proteins and structural genes, enables effective viral control without triggering excessive immune activation. In contrast, susceptible L. vannamei displays either widespread metabolic dysregulation leading to systemic collapse in moribund individuals or dependency on specific immune pathways (Toll-like receptor signaling and apoptosis) in survivors. Through comparative KEGG analysis, we identified heat shock protein 70 kDa (HSP70, K03283) as a key conserved gene and functionally validated its critical role in antiviral defense using RNA interference. Knockdown of HSP70 in M. nipponense significantly increased cumulative mortality and viral load, confirming its essential protective function. These findings provide novel insights into crustacean antiviral immunity and identify promising genetic targets for breeding WSSV-resistant shrimp strains, offering sustainable solutions for disease management in aquaculture. Full article

(This article belongs to the Special Issue Application of Germplasm Innovation Technology in Aquactic Genetic Breeding)

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23 pages, 1682 KB

Open AccessArticle

Experimental Mis-Splicing Assessment and ACMG/AMP-Guided Classification of 47 ATM Splice-Site Variants

by Inés Llinares-Burguet, Lara Sanoguera-Miralles, Elena Bueno-Martínez, Ada Esteban-Sanchez, Daniel Romano-Medina, Lobna Ramadane-Morchadi, Alicia García-Álvarez, Pedro Pérez-Segura, Doug F. Easton, Peter Devilee, Maaike P. G. Vreeswijk, Miguel de la Hoya and Eladio A. Velasco-Sampedro

Int. J. Mol. Sci. 2026, 27(2), 765; https://doi.org/10.3390/ijms27020765 - 12 Jan 2026

Abstract

Pathogenic germline variants in the ATM gene are associated with a 20–30% lifetime risk of breast cancer. Crucially, a relevant fraction of loss-of-function variants in breast cancer susceptibility genes disrupts pre-mRNA splicing. We aimed to perform splicing analysis of ATM splice-site variants identified [...] Read more.

Pathogenic germline variants in the ATM gene are associated with a 20–30% lifetime risk of breast cancer. Crucially, a relevant fraction of loss-of-function variants in breast cancer susceptibility genes disrupts pre-mRNA splicing. We aimed to perform splicing analysis of ATM splice-site variants identified in the large-scale sequencing project BRIDGES (Breast Cancer After Diagnostic Gene Sequencing). To this end, we bioinformatically selected 47 splice-site variants across 17 exons that were genetically engineered into three minigenes and assayed in MCF-7 cells. Aberrant splicing was observed in 38 variants. Of these, 30 variants, including 7 missense, yielded no or negligible expression of the minigene full-length (mgFL) transcript. A total of 69 different transcripts were characterized, 48 of which harboured a premature termination codon. Some variants, such as c.2922-1G>A, generated complex patterns with up to 10 different transcripts. Alternative 3′ or 5′ splice-site usage was the predominant event. Integration of ATM minigene read-outs into the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based specifications for the ATM gene enabled the classification of 30 ATM variants as pathogenic or likely pathogenic and 9 as likely benign. Overall, splicing assays provide key information for variant interpretation and the clinical management of patients. Full article

(This article belongs to the Special Issue Human Hereditary Diseases: Advances in Molecular Genetics, Genomics and Therapeutic Strategies)

16 pages, 1343 KB

Open AccessArticle

GPA33-Targeted Trimeric Immunotoxin Exhibits Enhanced Antitumor Activity in Human Colorectal Cancer Xenografts

by Javier Ruiz-de-la-Herrán, Javier Narbona, Rubén G. Gordo, Laura Sanz and Javier Lacadena

Int. J. Mol. Sci. 2026, 27(2), 764; https://doi.org/10.3390/ijms27020764 - 12 Jan 2026

Abstract

Immunotoxins are chimeric molecules with high potential as therapeutic candidates that combine antibody specificity to recognize and bind tumor-associated antigens and the cytotoxic potency of the enzymatic activity of a toxin, leading to the selective death of target cells. The use of immunotoxins [...] Read more.

Immunotoxins are chimeric molecules with high potential as therapeutic candidates that combine antibody specificity to recognize and bind tumor-associated antigens and the cytotoxic potency of the enzymatic activity of a toxin, leading to the selective death of target cells. The use of immunotoxins as therapeutic tools remains limited by various issues, such as selecting the appropriate tumor-associated antigen (TAA), penetration difficulties in solid tumors, low renal clearance, and low toxic payload. For this purpose, in this work we have designed a novel trimeric immunotoxin (IMTXTriA33αS) against colorectal cancer, combining the scFv against GPA33 as a targeting domain and the fungal ribotoxin α-sarcin (αS) as the toxic fragment, linked by a trimerization domain (TIE^XVIII). Our results demonstrate that IMTXTriA33αS has greater avidity and toxic load, showing a very significant increase in its in vitro and in vivo antitumor efficacy, due to its trimeric structure. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatment of Colorectal Cancer)

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53 pages, 4734 KB

Open AccessArticle

MGMT, NUPR1, NDRG2, and GLI1 Gene Promoter Methylation in Glioblastoma Tissues and Association with Clinical Characteristics and Therapeutic Outcomes

by Mariam M. Gabr, Sherihan G. AbdelHamid, Lobna R. Ezz El Arab, Menha Swellam and Nadia M. Hamdy

Int. J. Mol. Sci. 2026, 27(2), 763; https://doi.org/10.3390/ijms27020763 - 12 Jan 2026

Abstract

Glioblastoma (GBM) is the most prevalent and devastating form of primary brain tumors in adults, with dismal survival despite advancements in treatment modalities. The current study sought to develop clinically significant prognostic models for GBM patients by comprehensively profiling MGMT, NUPR1, NDRG2, and [...] Read more.

Glioblastoma (GBM) is the most prevalent and devastating form of primary brain tumors in adults, with dismal survival despite advancements in treatment modalities. The current study sought to develop clinically significant prognostic models for GBM patients by comprehensively profiling MGMT, NUPR1, NDRG2, and GLI1 gene promoter methylation in GBM tissues vs. non-neurooncological disease (NND) and their association with clinical characteristics and therapeutic outcome. This was further evaluated by in silico functional enrichment analysis. NUPR1, NDRG2, and GLI1 gene promoter methylation were significant epigenetic discriminators between GBM and NND. However, NDRG2 methylation was the sole independent predictor for neoplastic lesions (OR = 1.71, 95% CI [1.25–3.57], p = 0.028). Multivariable Cox regression analysis revealed that NUPR1 promoter hypermethylation was significantly correlated with a lower risk of mortality (HR = 0.96, 95% CI [0.96–0.99], p = 0.002), while multiple tumor sites were linked to an increased risk of mortality in the univariate model (HR = 4.44, 95% CI [1.42–13.88], p = 0.01). A heatmap correlation matrix identified a robust positive correlation among the MGMT and NUPR1 methylation status (r = 0.93, p < 0.001). NUPR1 and MGMT promoter hypermethylation was associated with a favorable response to temozolomide therapy. Patients with NUPR1 and MGMT hypermethylation exhibited extended OS and PFS compared to those with hypomethylation levels, whereas GLI1 and NDRG2 hypermethylation were linked to shorter PFS. In conclusion, the multi-faceted epigenetic panel adopted in the current study captures different aspects of GBM biology and moves towards a more comprehensive model that reflects the molecular heterogeneity of GBM as insights for personalized therapy. Full article

(This article belongs to the Section Molecular Biology)

25 pages, 1218 KB

Open AccessArticle

Aberrant Activation of the Hedgehog Pathway in Cutaneous Melanoma: Therapeutic Potential of Pharmacological Inhibitors

by F. Papaccio, D. Kovacs, R. Marrapodi, S. Caputo, E. Migliano, E. Melucci, S. Scalera, C. Cota, M. Maugeri-Saccà and B. Bellei

Int. J. Mol. Sci. 2026, 27(2), 762; https://doi.org/10.3390/ijms27020762 - 12 Jan 2026

Abstract

Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, [...] Read more.

Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, although the acquisition of resistance limits their effectiveness. Thus, new therapeutic approaches are needed. Emerging data indicate that the Hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly reactivated in melanoma and may represent a promising therapeutic target. Here, we demonstrate its chronic up-modulation in a panel of patient-derived cell lines and, by investigating the underlying molecular mechanisms, we excluded mutations in the principal components of the pathway. We observed reduced PTCH1 and SUFU repressors expression and GLI2 upregulation as common melanoma features. At the same time, copious SHH release, the principal PTCH1 ligand, evidenced autocrine Hh signaling activation. Consistently, a tendency of greater level of this factor resulted higher in the blood of patients compared to controls, confirming the relevance of ligand-dependent trigger in melanoma. The therapeutic potential of inhibiting the Hh pathway is highlighted by the reduced proliferation and migration observed in the presence of clinically approved pharmacological Hh antagonists. Profiling inflammatory mediators revealed significant modulation upon treatment with SMO inhibitors, possibly affecting chemotactic and immune functions. Collectively, these findings provide deeper insight into the role of the Hh pathway in melanoma and support the potential repurposing of Hh inhibitors as therapeutic agents for melanoma. Full article

(This article belongs to the Special Issue Skin Cancer: From Molecular Pathophysiology to Novel Treatment)

25 pages, 18702 KB

Open AccessArticle

Monopolar Radiofrequency for Facial Hyperpigmentation Treatment: An Integrated Retrospective Clinical Trial and Ex Vivo Study

by Yujin Baek, Ngoc Ha Nguyen, Seoyoon Ham, Wanjin Kim, Ju Hee Lee and Young In Lee

Int. J. Mol. Sci. 2026, 27(2), 761; https://doi.org/10.3390/ijms27020761 - 12 Jan 2026

Abstract

Aging-associated facial hyperpigmentation is driven not only by enhanced melanogenesis but also by dermal senescence and deterioration of the dermal–epidermal junction. The purpose of this study was to evaluate whether monopolar radiofrequency (MRF) monotherapy can improve aging-related facial hyperpigmentation by simultaneously suppressing melanogenic [...] Read more.

Aging-associated facial hyperpigmentation is driven not only by enhanced melanogenesis but also by dermal senescence and deterioration of the dermal–epidermal junction. The purpose of this study was to evaluate whether monopolar radiofrequency (MRF) monotherapy can improve aging-related facial hyperpigmentation by simultaneously suppressing melanogenic signaling and restoring senescence-associated dermal alterations. We assumed that deep dermal heating induced by MRF would modulate fibroblast senescence and basement membrane integrity, thereby indirectly regulating melanocyte activity. In a retrospective review of 26 Asian women, MRF treatment significantly decreased multiple pigmentation parameters, including melanin level, hyperconcentration, and Hemi Melasma Area and Severity Index (hemi-MASI) scores, while concurrently reducing wrinkles, pores, and enhanced overall skin texture without inducing inflammation. Complementary ex vivo experiments using ultraviolet B (UVB)-irradiated human skin demonstrated that MRF markedly reduced pro-melanogenic markers (α-MSH, MC1R, MITF, TYR, TRP1/2), restored collagen type IV expression at the basement membrane, decreased senescence-associated genes (p16, p21), and upregulated protective heat shock proteins (HSP70/47). Together, these findings suggest that MRF improves aging-associated hyperpigmentation by both suppressing melanogenesis and rejuvenating the senescent dermal microenvironment. MRF may serve as an effective non-invasive treatment option for pigmentation disorders in aging skin. Full article

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

24 pages, 1398 KB

Open AccessArticle

Potential of Fermented Food-Derived Lactiplantibacillus Cell-Free Supernatants to Control Staphylococcus aureus Growth and Biofilm Development

by Lena Ilieva, Vesselin Baev, Mariana Marhova, Galina Yahubyan, Elena Apostolova, Mariyana Gozmanova, Velizar Gochev, Tsvetelina Paunova-Krasteva, Tsvetozara Damyanova, Sonya Kostadinova, Miroslava Gocheva and Ivan Iliev

Int. J. Mol. Sci. 2026, 27(2), 760; https://doi.org/10.3390/ijms27020760 - 12 Jan 2026

Abstract

Staphylococcus aureus biofilms represent a critical healthcare challenge, driving chronic infections and antimicrobial resistance. This study investigates the anti-staphylococcal efficacy of two Lactiplantibacillus strains isolated from traditional Bulgarian pickled vegetables (turshiya): L. plantarum IZITR_24 and L. paraplantarum IZITR_13. Combining whole genome sequencing (WGS) [...] Read more.

Staphylococcus aureus biofilms represent a critical healthcare challenge, driving chronic infections and antimicrobial resistance. This study investigates the anti-staphylococcal efficacy of two Lactiplantibacillus strains isolated from traditional Bulgarian pickled vegetables (turshiya): L. plantarum IZITR_24 and L. paraplantarum IZITR_13. Combining whole genome sequencing (WGS) with functional assays, we established a robust genotype-to-phenotype framework to characterize their antimicrobial arsenal. Based on WGS, we identified conserved plantaricin (plnJK, plnEF) clusters in both isolates, with IZITR_13 additionally carrying genes for pediocin and enterolysin A—alongside the confirmed absence of virulence factors. Reconstituted lyophilized cell-free supernatants (LCFSs) were evaluated in dose–response microtiter assays to determine the minimum biofilm inhibitory concentration (MBIC) and minimum inhibitory concentration (MIC). Both strains demonstrated clear, dose-dependent inhibitory activity against the S. aureus growth and biofilm formation. Microscopy (SEM/CLSM) confirmed significant biofilm disruption and cell membrane permeabilization. The observed consistency between genome-inferred capacity and phenotypes highlights the strong predictive value of a genome-first screening approach for selecting bacteriocin-producing lactic acid bacteria (LAB). These findings position IZITR_24 and IZITR_13 as promising postbiotic producers with potent antibiofilm activity against S. aureus. By utilizing their stable postbiotic products rather than relying on live colonization, this study proposes a targeted, antibiotic-sparing strategy to combat persistent staphylococcal biofilms. Full article

(This article belongs to the Special Issue Antimicrobial Materials: Molecular Developments and Applications)

30 pages, 711 KB

Open AccessReview

A Systematic Review on GLP-1 Receptor Agonists in Reproductive Health: Integrating IVF Data, Ovarian Physiology and Molecular Mechanisms

by Charalampos Voros, Fotios Chatzinikolaou, Ioannis Papapanagiotou, Spyridon Polykalas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Georgios Papadimas, Charalampos Tsimpoukelis, Dimitrios Vaitsis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Nikolaos Kanakas, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(2), 759; https://doi.org/10.3390/ijms27020759 - 12 Jan 2026

Abstract

Women of reproductive age, especially those with polycystic ovarian syndrome (PCOS), often use glucagon-like peptide-1 receptor agonists (GLP-1RAs) to improve their metabolic functions. A growing body of evidence suggests that GLP-1R signaling may directly affect ovarian physiology, influencing granulosa cell proliferation, survival pathways, [...] Read more.

Women of reproductive age, especially those with polycystic ovarian syndrome (PCOS), often use glucagon-like peptide-1 receptor agonists (GLP-1RAs) to improve their metabolic functions. A growing body of evidence suggests that GLP-1R signaling may directly affect ovarian physiology, influencing granulosa cell proliferation, survival pathways, and steroidogenic production, in addition to its systemic metabolic effects. Nonetheless, there is a limited comprehension of the molecular mechanisms that regulate these activities and their correlation with menstrual function, reproductive potential, and assisted reproduction. This comprehensive review focuses on ovarian biology, granulosa cell signaling networks, steroidogenesis, and translational fertility outcomes, integrating clinical, in vivo, and in vitro information to elucidate the effects of GLP-1 receptor agonists on reproductive health. We conducted a thorough search of PubMed, Scopus, and Web of Science for randomized trials, prospective studies, animal models, and cellular experiments evaluating the effects of GLP-1RA on reproductive or ovarian outcomes, in accordance with PRISMA criteria. The retrieved data included metabolic changes, androgen levels, monthly regularity, ovarian structure, granulosa cell growth and death, FOXO1 signaling, FSH-cAMP-BMP pathway activity, and fertility or IVF results. Clinical trials shown that GLP-1 receptor agonists improve menstrual regularity, decrease body weight and central adiposity, increase sex hormone-binding globulin levels, and lower free testosterone in overweight and obese women with PCOS. Liraglutide, when combined with metformin, significantly improved IVF pregnancy rates, whereas exenatide increased natural conception rates. Mechanistic studies demonstrate that GLP-1R activation affects FOXO1 phosphorylation, hence promoting granulosa cell proliferation and anti-apoptotic processes. Incretin signaling altered steroidogenesis by reducing the levels of StAR, P450scc, and 3β-HSD, so inhibiting FSH-induced progesterone synthesis, while simultaneously enhancing BMP-Smad signaling. Animal studies demonstrated both beneficial (enhanced follicular growth, anti-apoptotic effects) and detrimental results (oxidative stress, granulosa cell death, uterine inflammation), indicating a context- and dose-dependent response. GLP-1 receptor agonists influence female reproductive biology by altering overall physiological processes and specifically impacting the ovaries via FOXO1 regulation, steroidogenic enzyme expression, and BMP-mediated FSH signaling. Preliminary clinical data indicate improved reproductive function in PCOS, as seen by increased pregnancy rates in both natural and IVF cycles; nevertheless, animal studies reveal a potential risk of ovarian and endometrial damage. These results highlight the need for controlled human research to clarify reproductive safety, molecular pathways, and optimum therapy timing, particularly in non-PCOS patients and IVF settings. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Physiology and Endocrinology)

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14 pages, 270 KB

Open AccessArticle

Genetic and Clinical Determinants of Chronic Thromboembolic Pulmonary Hypertension: The Role of PAI-1 Polymorphism

by Özgür Batum, Merve Ayık Türk, Yelda Varol, Berk Özyılmaz, Alp Eren Akarçay, Nigar Dirican, Sibel Doruk and Sami Deniz

Int. J. Mol. Sci. 2026, 27(2), 758; https://doi.org/10.3390/ijms27020758 - 12 Jan 2026

Abstract

Chronic thromboembolic pulmonary disease (CTEPD) is a severe long-term complication of acute pulmonary thromboembolism (PTE). Its pathogenesis is multifactorial, involving incomplete thrombus resolution, hemodynamic burden, comorbidities, and genetic factors. However, the contribution of inherited thrombophilic mutations to CTEPD development remains controversial. This retrospective [...] Read more.

Chronic thromboembolic pulmonary disease (CTEPD) is a severe long-term complication of acute pulmonary thromboembolism (PTE). Its pathogenesis is multifactorial, involving incomplete thrombus resolution, hemodynamic burden, comorbidities, and genetic factors. However, the contribution of inherited thrombophilic mutations to CTEPD development remains controversial. This retrospective cohort study included 204 patients diagnosed with acute PTE at a tertiary referral center between December 2023 and December 2024. Baseline demographic, clinical, laboratory, and echocardiographic data were collected. Genetic analysis assessed Factor II, Factor V Leiden, MTHFR C677T, MTHFR A1298C, Factor XIII V34L, and PAI-1 4G/5G polymorphisms. Patients were followed for at least 12 months for the development of CTEPD, defined according to guideline-based hemodynamic and imaging criteria. During follow-up, 17 patients (8.3%) developed CTEPD. Patients with CTEPD were significantly older and had higher baseline and follow-up systolic pulmonary artery pressure (sPAP) (p < 0.001), elevated NT-proBNP and troponin levels (both p < 0.001), and more frequent comorbidities, including cardiac and renal disease. Multivariate logistic regression identified comorbid diseases (HR: 0.17, 95% CI: 0.039–0.80, p = 0.025) and genetic thrombophilic factors (HR: 0.30, 95% CI: 0.10–0.91, p = 0.034) as independent predictors. Among genetic variants, only the PAI-1 4G/5G polymorphism was significantly associated with CTEPD (p = 0.001). Our study demonstrates that advanced age, comorbid diseases, elevated cardiac biomarkers, and genetic predisposition are associated with the development of CTEPD after acute PTE, while the PAI-1 4G/5G polymorphism may contribute to CTEPD susceptibility within a multifactorial context. Full article

(This article belongs to the Special Issue Coagulation Factors and Natural Anticoagulants in Health and Disease)

15 pages, 2652 KB

Open AccessArticle

Cannabidiol as a Prophylactic Agent Against Glioblastoma Growth: A Preclinical Investigation

by Lei P. Wang, Bidhan Bhandari, Sahar Emami Naeini, Breanna Hill, Hannah M. Rogers, Jules Gouron, Nayeli Perez-Morales, Aruba Khan, William Meeks, Ahmed El-Marakby, Nancy Young, Fernando L. Vale, Salman Ali, Gerald Wallace, Jack C. Yu, Ali S. Arbab, Évila Lopes Salles and Babak Baban

Int. J. Mol. Sci. 2026, 27(2), 757; https://doi.org/10.3390/ijms27020757 - 12 Jan 2026

Abstract

Glioblastoma (GBM) remains one of the most lethal brain tumors, with current therapies offering limited benefits and high relapse rates. This study presents the first preclinical evidence that pretreatment with inhaled cannabidiol (CBD) before tumor establishment can markedly inhibit GBM progression. We hypothesized [...] Read more.

Glioblastoma (GBM) remains one of the most lethal brain tumors, with current therapies offering limited benefits and high relapse rates. This study presents the first preclinical evidence that pretreatment with inhaled cannabidiol (CBD) before tumor establishment can markedly inhibit GBM progression. We hypothesized that early CBD exposure could prime the immune and molecular landscape to resist tumor growth. C57BL/6 mice were pretreated with inhaled CBD for 3 or 14 days, or with placebo, prior to intracranial implantation of glioblastoma cells. Tumor growth, immune checkpoint expressions (IDO, PD-L1), and key biomarkers (MGMT, Ki67) were analyzed to evaluate tumor dynamics and immune modulation. Fourteen-day CBD pretreatment significantly reduced tumor burden compared with both placebo and 3-day CBD groups, accompanied by decreased IDO, PD-L1, MGMT, and Ki67 expression, which are signatures of a less aggressive tumor phenotype. These findings suggest that prolonged CBD exposure can precondition the tumor microenvironment toward an anti-tumor state, improving disease control and potentially lowering relapse risk. This study introduces a novel concept of CBD pretreatment as an immune-modulatory strategy with high translational potential for glioblastoma management. Full article

(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)

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31 pages, 2128 KB

Open AccessReview

RNA-Binding Proteins in Adipose Biology: From Mechanistic Understanding to Therapeutic Opportunities

by Ghida Dairi, Maria Al Ibrahim, Saeed Al Mahri, Khalid Al-Regaiey, Shuja Shafi Malik and Sameer Mohammad

Int. J. Mol. Sci. 2026, 27(2), 756; https://doi.org/10.3390/ijms27020756 - 12 Jan 2026

Abstract

Obesity, defined by excessive body fat accumulation, is strongly associated with dysfunction of adipose tissue, a major regulator of whole-body energy balance and metabolic health. Dysfunctional adipose tissue is characterized by altered adipokine secretion, impaired insulin sensitivity, and chronic low-grade inflammation, all of [...] Read more.

Obesity, defined by excessive body fat accumulation, is strongly associated with dysfunction of adipose tissue, a major regulator of whole-body energy balance and metabolic health. Dysfunctional adipose tissue is characterized by altered adipokine secretion, impaired insulin sensitivity, and chronic low-grade inflammation, all of which contribute to obesity-related comorbidities such as type 2 diabetes, cardiovascular disease, and certain cancers. Understanding how obesity disrupts adipose tissue biology is essential for developing strategies to mitigate these metabolic risks. In recent years, RNA-binding proteins (RBPs) have emerged as important regulators of energy metabolism. By controlling post-transcriptional gene expression, RBPs influence RNA stability, localization, and translation, thereby shaping key cellular processes. Dysregulation of specific RBPs has been implicated in obesity and metabolic disorders, with several shown to affect adipogenesis, lipid handling, thermogenesis, and insulin sensitivity across different adipose depots. Their ability to direct the fate of transcripts involved in metabolic homeostasis positions RBPs as critical nodes linking adipose dysfunction to systemic disease. This review provides a mechanistic overview of RBP functions in adipose biology, highlights how their dysregulation can reinforce metabolic dysfunction, and identifies gaps and future directions for exploring RBPs and their RNA networks as potential therapeutic targets for obesity and related metabolic diseases. Full article

(This article belongs to the Special Issue Molecular and Cellular Research on Adipose Tissue Development and Functions, 2nd Edition)

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17 pages, 5357 KB

Open AccessArticle

Thrombospondin 1–CD47 Signalling Modulates Vascular Smooth Muscle Cell Senescence in Chronic Kidney Disease

by Katie Trinh, Sally Coulter, Cuicui Xu, Nadia Chandra Sekar, Sohel M. Julovi and Natasha M. Rogers

Int. J. Mol. Sci. 2026, 27(2), 755; https://doi.org/10.3390/ijms27020755 - 12 Jan 2026

Abstract

Chronic kidney disease (CKD) accelerates vascular dysfunction and cardiovascular disease, partly through the accumulation of the uraemic toxin indoxyl sulphate (IS). Thrombospondin-1 (TSP1) and its receptor CD47 have been implicated in vascular pathology, but their role in CKD-associated vascular remodelling is unknown. We [...] Read more.

Chronic kidney disease (CKD) accelerates vascular dysfunction and cardiovascular disease, partly through the accumulation of the uraemic toxin indoxyl sulphate (IS). Thrombospondin-1 (TSP1) and its receptor CD47 have been implicated in vascular pathology, but their role in CKD-associated vascular remodelling is unknown. We investigated the contribution of TSP1–CD47 signalling to vascular smooth muscle cell (VSMC) dysfunction in CKD. Human aortic VSMCs (hVSMCs) were exposed to IS, TSP1, or plasma from patients with CKD. CKD was induced in wild-type (WT) and CD47-deficient (CD47KO) mice using 5/6 nephrectomy. Vascular changes were assessed by histology, immunohistochemistry, and molecular analyses. IS, TSP1, and CKD plasma increased TSP1 expression in hVSMCs, reduced proliferation, elevated β-galactosidase activity, and activated phosphorylated ERK1/2 and cytoplasmic aryl hydrocarbon receptor. These effects were attenuated by CD47 blockade. CKD plasma further enhanced IS- and TSP1-induced senescence. In vivo, 5/6 nephrectomy induced aortic wall thickening in WT but not in CD47KO mice. Aortic pERK1/2 was reduced in CD47KO mice despite persistent TSP1 upregulation. IS and TSP1 promote VSMC senescence through CD47-dependent ERK1/2 and AhR signalling. CD47 deletion protects against CKD-induced vascular remodelling, suggesting that CD47 blockade may represent a novel therapeutic strategy to mitigate vascular complications in CKD. Full article

(This article belongs to the Special Issue Molecular Research on Chronic Kidney Disease)

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36 pages, 1746 KB

Open AccessReview

Cross-Talk Between Signaling and Transcriptional Networks Regulating Thermogenesis—Insights into Canonical and Non-Canonical Regulatory Pathways

by Klaudia Simka-Lampa

Int. J. Mol. Sci. 2026, 27(2), 754; https://doi.org/10.3390/ijms27020754 - 12 Jan 2026

Abstract

Brown adipose tissue (BAT) and beige adipocytes play a crucial role in adaptive thermogenesis, primarily via uncoupling protein 1 (UCP1)-driven heat production. Once considered physiologically irrelevant in adults, BAT is now recognized as an active tissue that contributes to energy expenditure and metabolic [...] Read more.

Brown adipose tissue (BAT) and beige adipocytes play a crucial role in adaptive thermogenesis, primarily via uncoupling protein 1 (UCP1)-driven heat production. Once considered physiologically irrelevant in adults, BAT is now recognized as an active tissue that contributes to energy expenditure and metabolic homeostasis and represents a potential therapeutic target for obesity and metabolic disorders. This review provides an integrated overview of the molecular regulation of thermogenic adipocytes, emphasizing both canonical UCP1-dependent as well as non-canonical UCP1-independent mechanisms of heat generation. Key transcriptional and epigenetic regulators are discussed in the context of mitochondrial biogenesis, substrate utilization, and thermogenic gene programs. Major upstream signaling routes are further summarized, encompassing classical β-adrenergic pathways, as well as alternative regulatory nodes including AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) together with diverse nutrient- and hormone-responsive cues that converge to activate brown and beige adipocytes. Finally, the cross-talk among neuronal, endocrine, immune, and gut microbiota-derived signals is highlighted as a key determinant of thermogenic adipocyte function. Together, these multilayered regulatory inputs provide a comprehensive framework for understanding how thermogenic adipose tissue integrates environmental, metabolic, and microbial cues to regulate systemic energy balance—knowledge that is essential for developing targeted therapies to combat obesity and metabolic diseases. Full article

(This article belongs to the Special Issue Regulation of Brown Adipose Function)

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17 pages, 872 KB

Open AccessReview

Natural Compounds in Gastric Cancer Therapy: Molecular Mechanisms and Potential Treatment Options

by Alexandra Dimaki, Lydia Lazaridou, Kalliopi Vakalou, Vasilios Zervas, Dimitra Bartzi, Kyriaki Tsagkidou, Panagiotis Dimitrios Papadopoulos, Konstantinos Eleftherios Koumarelas and Grigorios Christodoulidis

Int. J. Mol. Sci. 2026, 27(2), 753; https://doi.org/10.3390/ijms27020753 - 12 Jan 2026

Abstract

Gastric cancer (GC) is the fifth most common type of cancer and a leading cause of cancer-related deaths worldwide. Surgery remains the most effective treatment, but new therapeutic strategies are urgently needed. The use of natural polyphenolic compounds such as curcumin (CUR) and [...] Read more.

Gastric cancer (GC) is the fifth most common type of cancer and a leading cause of cancer-related deaths worldwide. Surgery remains the most effective treatment, but new therapeutic strategies are urgently needed. The use of natural polyphenolic compounds such as curcumin (CUR) and resveratrol (RSV) has played a significant role in this effort. This review provides a comprehensive overview of the current applications and molecular mechanisms of curcumin and resveratrol in gastric cancer, highlighting their therapeutic potential and translational relevance. Analytically, CUR induces apoptosis, endoplasmic stress and cell cycle arrest. On the other hand, resveratrol enhances apoptosis and reduces inflammation. Both compounds increase cancer cell sensitivity to chemotherapy and help prevent chemoresistance, highlighting their potential as molecular enhancers in anticancer therapy. Combined with standard therapeutic drugs, they represent an innovative strategy for GC treatment. By presenting these innovative approaches, this review offers a global perspective on how their administration could shape future treatment strategies. Full article

(This article belongs to the Special Issue Natural Compounds in Cancer Therapy: Molecular Mechanisms and Translational Potential)

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13 pages, 733 KB

Open AccessReview

G Protein-Coupled Receptors in Irritable Bowel Syndrome: Mechanisms and Therapeutic Opportunities

by Zhenya Zhu, Ziyu Liu, Yate He, Xiaorui He, Wei Zheng and Mizu Jiang

Int. J. Mol. Sci. 2026, 27(2), 752; https://doi.org/10.3390/ijms27020752 - 12 Jan 2026

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain, altered motility, and visceral hypersensitivity. Emerging evidence implicates G protein-coupled receptors (GPCRs) as key integrators of microbial, immune, endocrine, and neural signals in IBS pathophysiology. This review summarizes recent advances [...] Read more.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain, altered motility, and visceral hypersensitivity. Emerging evidence implicates G protein-coupled receptors (GPCRs) as key integrators of microbial, immune, endocrine, and neural signals in IBS pathophysiology. This review summarizes recent advances in understanding how GPCRs mediate gut immune regulation, microbiota–host crosstalk, metabolic signaling, and pain processing in IBS. Recent studies show that microbial metabolites (e.g., short-chain fatty acids, biogenic amines, and lipid mediators) signal through GPCRs on immune cells, epithelia, and neurons to influence intestinal homeostasis. On immune cells and neurons, GPCRs also mediate signals from external substances (such as fats, sugars, histamine, etc.) to regulate immune and neural functions. And there are challenges and future directions in targeting GPCRs for IBS, including patient heterogeneity and the complexity of host–microbiome interactions. This review provides a mechanistic framework for GPCR-based therapies in IBS. Full article

(This article belongs to the Special Issue Emerging Roles of the Gut-Brain Axis (GBA) in Health and Disease)

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3 pages, 156 KB

Open AccessEditorial

Special Issue “Transcriptional Regulation in Plant Development: 2nd Edition”

by Konstantinos E Vlachonasios

Int. J. Mol. Sci. 2026, 27(2), 751; https://doi.org/10.3390/ijms27020751 - 12 Jan 2026

Abstract

The following Special Issue highlights the sophisticated transcriptional regulatory networks governing plant development, with a specific focus on how genetic, epigenetic, and metabolic pathways integrate environmental signals to shape agronomic traits [...] Full article

(This article belongs to the Special Issue Transcriptional Regulation in Plant Development: 2nd Edition)

13 pages, 1783 KB

Open AccessArticle

Machine-Learning–Based Prediction of Biochemical Recurrence in Prostate Cancer Integrating Fatty-Acid Metabolism and Stemness

by Zao Dai, Ningrui Wang, Mengyao Liu, Zhenguo Wang and Guanyun Wei

Int. J. Mol. Sci. 2026, 27(2), 750; https://doi.org/10.3390/ijms27020750 - 12 Jan 2026

Abstract

Prostate cancer (PCa) is a common malignancy among men worldwide. After radical prostatectomy (RP) and radical radiotherapy (RT), patients may experience biochemical recurrence (BCR) of prostate cancer, indicating disease progression. Therefore, it is meaningful to predict and accurately assess the risk of BCR, [...] Read more.

Prostate cancer (PCa) is a common malignancy among men worldwide. After radical prostatectomy (RP) and radical radiotherapy (RT), patients may experience biochemical recurrence (BCR) of prostate cancer, indicating disease progression. Therefore, it is meaningful to predict and accurately assess the risk of BCR, and a machine-learning-based-model for BCR prediction in PCa based on fatty-acid metabolism and cancer-cell stemness was developed. A stemness prediction model and ssGSEA (single-sample gene set enrichment analysis) empirical cumulative distribution function algorithm were used to score the stemness scoring (mRNAsi) and fatty-acid metabolism of prostate-cancer samples, respectively, and further analysis showed that the two scores of the samples were positively correlated. Based on WGCNA (weighted correlation network analysis), we discovered modules significantly associated with both stemness and fatty-acid metabolism and obtained the genes within them. Then, based on this gene set, 101 algorithm combinations of 10 machine-learning methods were used for training and prediction BCR of PCa, and the model with the best prediction effect was named fat_stemness_BCR. Compared with 23 published PCa BCR models, the fat_stemness_BCR model performs better in TCGA and CPGEA data. To facilitate the use of the model, the trained model was encapsulated into an R package and an online service tool (PCaMLmodel, Version 1.0) was built. The newly developed fat_stemness_SCR model enriches the prognostic research of biochemical recurrence in PCa and provides a new reference for the study of other diseases. Full article

(This article belongs to the Special Issue Latest Molecular Advances in Prostate Cancer)

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44 pages, 1586 KB

Open AccessReview

Socceromics: A Systematic Review of Omics Technologies to Optimize Performance and Health in Soccer

by Adam Owen, Halil İbrahim Ceylan, Piotr Zmijewski, Carlo Biz, Giovanni Sciarretta, Alessandro Rossin, Pietro Ruggieri, Andrea De Giorgio, Carlo Trompetto, Nicola Luigi Bragazzi and Luca Puce

Int. J. Mol. Sci. 2026, 27(2), 749; https://doi.org/10.3390/ijms27020749 - 12 Jan 2026

Abstract

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines [...] Read more.

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., ACE, AGT, NOS3, VEGF, ADRA2A, ADRB1–3) were associated with endurance, cardiovascular regulation, and recovery. Genes related to muscle structure, metabolism, and hypertrophy (e.g., ACTN3, CKM, MLCK, TRIM63, TTN-AS1, HIF1A, MSTN, MCT1, AMPD1) were linked to sprint performance, metabolic efficiency, and muscle injury susceptibility. Neurotransmission-related genes (BDNF, COMT, DRD1–3, DBH, SLC6A4, HTR2A, APOE) influenced motivation, fatigue, cognitive performance, and brain injury recovery. Connective tissue and extracellular matrix genes (COL1A1, COL1A2, COL2A1, COL5A1, COL12A1, COL22A1, ELN, EMILIN1, TNC, MMP3, GEFT, LIF, HGF) were implicated in ligament, tendon, and muscle injury risk. Energy metabolism and mitochondrial function genes (PPARA, PPARG, PPARD, PPARGC1A, UCP1–3, FTO, TFAM) shaped endurance capacity, substrate utilization, and body composition. Oxidative stress and detoxification pathways (GSTM1, GSTP1, GSTT1, NRF2) influenced recovery and resilience, while bone-related variants (VDR, P2RX7, RANK/RANKL/OPG) were associated with bone density and remodeling. Beyond genomics, proteomics identified markers of muscle damage and repair, metabolomics characterized fatigue- and energy-related signatures, and microbiomics revealed links between gut microbial diversity, recovery, and physiological resilience. Evidence from omics research in soccer supports the potential for individualized approaches to training, nutrition, recovery, and injury prevention. By integrating genomics, proteomics, metabolomics, and microbiomics data, clubs and sports practitioners may design precision strategies tailored to each player’s biological profile. Future research should expand on multi-omics integration, explore gene–environment interactions, and improve representation across sexes, age groups, and competitive levels to advance precision sports medicine in soccer. Full article

(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)

20 pages, 6259 KB

Open AccessArticle

Plant-Derived miR-55 Alleviates Liver Fibrosis by Disrupting the CK2α/SMO Complex and Promoting SMO Ubiquitination

by Lei Wu, Jing Yang, Anqi Li, Yuqiang Zhao, Qing Liu, Zhenbo Li, Yihan Liu, Peng Tang and Rui Wang

Int. J. Mol. Sci. 2026, 27(2), 748; https://doi.org/10.3390/ijms27020748 - 12 Jan 2026

Abstract

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of [...] Read more.

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 2708 KB

Open AccessReview

Berberine: A Negentropic Modulator for Multi-System Coordination

by Xiaolian Tian, Qingbo Chen, Yingying He, Yangyang Cheng, Mengyu Zhao, Yuanbin Li, Meng Yu, Jiandong Jiang and Lulu Wang

Int. J. Mol. Sci. 2026, 27(2), 747; https://doi.org/10.3390/ijms27020747 - 12 Jan 2026

Abstract

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity [...] Read more.

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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26 pages, 4165 KB

Open AccessArticle

Spectroscopic Methods in Evaluation of Antioxidant Potential, Enzyme Inhibition, Cytotoxicity, and Antimicrobial Activity of the Synthesized N³-Substituted Amidrazones

by Renata Paprocka, Leszek Pazderski, Jolanta Kutkowska, Iqra Naeem, Amna Shahid Awan, Zahid Mushtaq and Aleksandra Szydłowska-Czerniak

Int. J. Mol. Sci. 2026, 27(2), 746; https://doi.org/10.3390/ijms27020746 - 12 Jan 2026

Abstract

Seven amidrazones containing a characteristic NH₂–N=C(Ar¹)–NHAr² moiety, where Ar¹, Ar² are phenyl, 4-methylphenyl, 4-nitrophenyl, 2-pyridyl, and 4-pyridyl substituents, denoted as 2a–2g, were synthesized by the reactions between thioamides and hydrazine. Their molecular [...] Read more.

Seven amidrazones containing a characteristic NH₂–N=C(Ar¹)–NHAr² moiety, where Ar¹, Ar² are phenyl, 4-methylphenyl, 4-nitrophenyl, 2-pyridyl, and 4-pyridyl substituents, denoted as 2a–2g, were synthesized by the reactions between thioamides and hydrazine. Their molecular structures were confirmed by ¹H, ¹³C, ¹H-¹³C HMQC, ¹H-¹³C HMBC, and ¹H-¹⁵N HMBC NMR spectroscopy, with complete assignment of the detected signals, as well as by high-resolution mass spectra. The biological activity of all compounds was studied, exhibiting antioxidant properties determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) methods, inhibitory potential against digestive tract enzymes (α-amylase, lipase, pepsin), cytotoxicity (hemolysis), and antimicrobial activities (against Gram-positive and Gram-negative bacteria, and a fungus). The antioxidant activity of the studied amidrazones varied from 83.34% to 93.27% and 1.01–5.79 mM FeSO₄ for the DPPH and FRAP methods, respectively. Moreover, these derivatives revealed inhibition potential against α-amylase (28.6–86.8%), lipase (28.0–60.0%), and pepsin (34.1–76.6%), which increased when increasing their concentrations from 0.2 to 1 mg/mL. Among them, compound 2d (possessing 2-pyridyl and 4-nitrophenyl substituents) stood out in particular, as a potent antioxidant (DPPH = 90.43%, FRAP = 4.73 Mm FeSO₄) with the highest activity against Gram-positive bacteria: S. aureus (MIC = 64 μg/mL), G. rubripertincta (MIC = 64 μg/mL), and fungus: C. albicans (MIC = 32 μg/mL); high α-amylase (86.8%) inhibition at the highest concentration (1 mg/mL); and lipase (38.0%) and pepsin (43.8%) inhibition at the lowest concentration (0.2 mg/mL). The obtained results were analyzed by unsupervised multivariate techniques to confirm significant differences in the biological activity of amidrazones depending on the Ar¹ and Ar² substituents. Full article

(This article belongs to the Special Issue Spectroscopic Techniques in Molecular Sciences)

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14 pages, 947 KB

Open AccessReview

A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction

by Emma Lugli, Ludovica Gaiaschi, Maria Grazia Bottone and Fabrizio De Luca

Int. J. Mol. Sci. 2026, 27(2), 745; https://doi.org/10.3390/ijms27020745 - 12 Jan 2026

Abstract

Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan [...] Read more.

Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan implications: the accumulation of misfolded collagen can induce persistent endoplasmic reticulum stress, which can in turn compromise mitochondrial function and autophagy or lead to cell death activation, and it can even promote widespread redox imbalance and inflammation. The interplay between intracellular stress, widespread oxidative damage and inflammation not only underlies cellular dysfunction but also the multisystemic manifestations of osteogenesis imperfecta. Targeting these interconnected pathways may result in new insights for a better understanding of OI and possibly offer novel therapeutic strategies designed to restore proteostasis and improve cell homeostasis and overall patient outcomes, highlighting the need for an integrated understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease and their translation into patient-centred therapeutic interventions. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 1028 KB

Open AccessArticle

Who Am I? Eyebrow Follicles Minimize Donor-Derived DNA for Germline Testing After Hematopoietic Stem Cell Transplantation

by Matthias Mertens, Mona Sadlo, Jörn-Sven Kühl, Klaus Metzeler, Louisa Zschenderlein, Jeanett Edelmann, Claudia Lehmann, Sarah Thull, Mert Karakaya, Clara Velmans, Theresa Tumewu, Matthias Böhme, Christina Klötzer, Anne Weigert, Vladan Vucinic, Julia Hentschel and Mareike Mertens

Int. J. Mol. Sci. 2026, 27(2), 744; https://doi.org/10.3390/ijms27020744 - 12 Jan 2026

Abstract

Germline genetic testing plays a critical role in diagnosing inherited predispositions and increasingly guides therapeutic and surveillance choices—but becomes technically challenging after allogeneic hematopoietic stem cell transplantation (HSCT), when donor-derived DNA contaminates host tissues. To address this, we compared donor-derived DNA across three [...] Read more.

Germline genetic testing plays a critical role in diagnosing inherited predispositions and increasingly guides therapeutic and surveillance choices—but becomes technically challenging after allogeneic hematopoietic stem cell transplantation (HSCT), when donor-derived DNA contaminates host tissues. To address this, we compared donor-derived DNA across three accessible tissues—buccal swab, nail, and eyebrow follicles—in recipients after hematopoietic stem cell transplantation using two orthogonal assays (34-SNP next-generation sequencing and a 27-marker short tandem repeat panel) and modeled clinical covariates that influence chimerism. Eyebrow follicles showed consistently low donor DNA (median 1% by NGS; 3% by STR) whereas buccal swabs and nails carried substantially higher donor fractions (+25 and +22 percentage points versus eyebrow, respectively; both p < 0.01). Across methods, STR yielded on average ≈6 percentage points higher donor fractions than NGS at low-level chimerism. Several transplant covariates correlated with chimerism: matched-related donors and a perfect HLA match (10/10) were each associated with lower donor DNA (≈12–14 and 15–20 percentage points, respectively); longer times since hematopoietic stem cell transplantation correlated with lower levels for nail samples, and donor–recipient sex match correlated with higher donor DNA (~7–8 percentage points). Even low-level chimerism can distort germline variant interpretation. We propose a pragmatic protocol for post-hematopoietic stem cell transplantation germline testing that prioritizes eyebrow follicles as the default tissue. An SNP-based quality control assay is used to flag unsafe donor fractions (≥ 5–10%) before comprehensive germline analysis, reducing the risk that chimeric donor DNA distorts germline variant interpretation. Full article

(This article belongs to the Special Issue Innovative Approaches in Personalized Medicine: Cancer, Inherited Diseases, and Beyond)

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2 pages, 895 KB

Open AccessCorrection

Correction: Bajbouj et al. Synergistic Anti-Angiogenic Effect of Combined VEGFR Kinase Inhibitors, Lenvatinib, and Regorafenib: A Therapeutic Potential for Breast Cancer. Int. J. Mol. Sci. 2022, 23, 4408

by Khuloud Bajbouj, Rizwan Qaisar, Mohammed A. Alshura, Zeinab Ibrahim, Mohamad B. Alebaji, Amenah W. Al Ani, Hanadi M. Janajrah, Mariah M. Bilalaga, Abdelrahman I. Omara, Rebal S. Abou Assaleh, Maha M. Saber-Ayad and Adel B. Elmoselhi

Int. J. Mol. Sci. 2026, 27(2), 743; https://doi.org/10.3390/ijms27020743 - 12 Jan 2026

Abstract

Figure 3A has been updated to replace an inadvertent duplication from Figure 3B [...] Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 1365 KB

Open AccessArticle

Synthesis, Antimicrobial Evaluation, and Molecular Docking Analysis of Novel Schiff Bases Derived from Isatoic Anhydride and Salicylaldehyde

by Turgay Tunç and Yaşar Köse

Int. J. Mol. Sci. 2026, 27(2), 742; https://doi.org/10.3390/ijms27020742 - 11 Jan 2026

Abstract

Schiff bases are bioactive compounds that have been synthesized by many researchers in recent years. They may also exhibit strong antimicrobial activities against various pathogenic microorganisms in both medicine and veterinary applications. The synthesis of new Schiff base-derived compounds remains of interest due [...] Read more.

Schiff bases are bioactive compounds that have been synthesized by many researchers in recent years. They may also exhibit strong antimicrobial activities against various pathogenic microorganisms in both medicine and veterinary applications. The synthesis of new Schiff base-derived compounds remains of interest due to the increasing problem of antibiotic-resistance in clinical practice. Seven new Schiff base derivatives were synthesized, and their chemical structures were characterized using FT-IR, ¹H/¹³C NMR, and LCMS-MS analyses. The antimicrobial activities of thesyntesized compounds against various pathogenic bacteria, yeasts, and fungi were evaluated using the disk-diffusion method, and their MIC values were also determined. In addition, one representative microorganisms from each class were selected for molecular docking studies. IFD analyses were performed for the 4f and 4g ligands using the dihydrofolate reductase enzyme. Spectroscopic analyses confirmed the structures of the synthesized compounds, revealing the presence of characteristic imine functionalities and validating the integrity of the molecular frameworks. Antimicrobial assays demonstrated that several derivatives exhibited measurable activity, with compounds 4f and 4g showing the most potent effects, displaying MIC values of 32 µg/mL against B. cereus and E. faecalis, respectively. Molecular docking studies further indicated that both 4f and 4g bind efficiently to the DHFR active site. These findings indicate that among the synthesized Schiff base derivatives, compounds 4f and 4g exhibit particularly promising antimicrobial activity, warranting further pharmacological evaluation and medicinal chemistry optimization. Full article

(This article belongs to the Section Physical Chemistry and Chemical Physics)

10 pages, 902 KB

Open AccessArticle

The Phylogenomic Approach Suggests That Butyrophilins Have Ligands Beyond Gamma–Delta Receptors

by Ludovic Marenco, Daniel Olive and Pierre Pontarotti

Int. J. Mol. Sci. 2026, 27(2), 741; https://doi.org/10.3390/ijms27020741 - 11 Jan 2026

Abstract

Since γδ T cells are present in all jawed vertebrates, we wondered whether butyrophilins, proteins that play a key role in the activation of these cells, were also present in these organisms. Our analyses revealed the presence of genes encoding butyrophilins across all [...] Read more.

Since γδ T cells are present in all jawed vertebrates, we wondered whether butyrophilins, proteins that play a key role in the activation of these cells, were also present in these organisms. Our analyses revealed the presence of genes encoding butyrophilins across all jawed vertebrates, including in squamates, a reptilian clade that is nonetheless reported in the literature to have lost γδ T cells. The conservation of butyrophilins in this group, despite the absence of their only known cellular partner, suggests that they may fulfill an alternative function, possibly through interaction with another ligand. Given their strong conservation across jawed vertebrates, it is reasonable to hypothesize that this alternative ligand may also be present in humans. Full article

(This article belongs to the Section Molecular Immunology)

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15 pages, 2175 KB

Open AccessArticle

Analysis of Soft Tissue N-Glycome Profiles in Oral Squamous Cell Carcinoma, a Pilot Study

by Eniko Gebri, Kinga Hogyor, Adrienne Szabo and Andras Guttman

Int. J. Mol. Sci. 2026, 27(2), 740; https://doi.org/10.3390/ijms27020740 - 11 Jan 2026

Abstract

Oral squamous cell carcinoma (OSCC) is an aggressive disease with a glycoproteomically unmapped progression and a low five-year survival rate. Thus, the aim of this pilot study was to explore the N-glycosylation pattern differences in malignant, adjacent mucosal and healthy tissues in the [...] Read more.

Oral squamous cell carcinoma (OSCC) is an aggressive disease with a glycoproteomically unmapped progression and a low five-year survival rate. Thus, the aim of this pilot study was to explore the N-glycosylation pattern differences in malignant, adjacent mucosal and healthy tissues in the context of OSCC. Oral mucosal soft tissue samples was obtained by incisional biopsy from five patients with OSCC, both from the malignant and the opposite healthy gingival sides, and from seven age-sex-matched healthy controls. The collected tissues were homogenized, followed by N-glycan profiling of the endoglycosidase-released and fluorophore-labeled carbohydrates using capillary electrophoresis with ultra-sensitive laser-induced fluorescent detection (CE-LIF). Six out of the twenty-two identified N-glycan structures, including glycogens, showed significant (p < 0.05) differences between the malignant tissue samples of the OSCC patients and the healthy controls. Comparing the healthy and the positive control oral mucosal samples, differences in four N-glycan structures were revealed, while only one alteration was observed between the N-glycan profiles of the malignant tumor and positive control samples. However, the results are presented descriptively, reflecting the limited sample size of the pilot study, it shows the potential of high-resolution CE-LIF-based glyocoanalytical protocol to be highly efficient and sensitive for glycobiomarker-based molecular diagnostics of oral malignant lesions. Full article

(This article belongs to the Special Issue Oral Potentially Malignant Disorders and Oral Cancers: From Molecular Pathology to Therapeutic Approaches)

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Int. J. Mol. Sci., Volume 27, Issue 2 (January-2 2026) – 214 articles

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