International Journal of Molecular Sciences

14 pages, 692 KB

Open AccessArticle

Soluble Dietary Fiber from Polygonatum cyrtonema Hua Attenuates Cyclophosphamide-Induced Intestinal Injury in Mice

by Lingqiao Zeng, Shengxin Cui and Teng Peng

Int. J. Mol. Sci. 2026, 27(10), 4537; https://doi.org/10.3390/ijms27104537 (registering DOI) - 18 May 2026

This study aimed to evaluate the protective effects of soluble dietary fiber (SDF) derived from Polygonatum cyrtonema Hua residues on cyclophosphamide (CTX)-induced intestinal injury in mice. A total of 60 C57BL/6 mice (6–8 weeks old; body weight, 23.8 ± 0.5 g) were randomly [...] Read more.

This study aimed to evaluate the protective effects of soluble dietary fiber (SDF) derived from Polygonatum cyrtonema Hua residues on cyclophosphamide (CTX)-induced intestinal injury in mice. A total of 60 C57BL/6 mice (6–8 weeks old; body weight, 23.8 ± 0.5 g) were randomly allocated to six groups (n = 10 per group): a control group (CON), a CTX model group (CTX), a levamisole-treated positive control group (PC), and low-, medium-, and high-dose SDF groups (125, 250, and 500 mg/kg body weight, respectively). Mice received oral administration of SDF or an equal volume of water for 21 consecutive days and were intraperitoneally injected with CTX (80 mg/kg body weight) on days 19–21 to induce intestinal injury. The results demonstrate that SDF possessed a porous, sponge-like network structure and comprised multiple monosaccharides. SDF intervention, particularly at medium and high doses, significantly attenuated CTX-induced body weight loss and immune organ atrophy; restored villus height and the villus-to-crypt ratio; increased the numbers of goblet cells and intraepithelial lymphocytes; elevated intestinal levels of sIgA, β-defensins, and lysozyme; and reduced serum levels of LPS, D-lactic acid, and DAO (p < 0.05). In conclusion, SDF derived from Polygonatum cyrtonema effectively mitigates CTX- Full article

(This article belongs to the Special Issue Molecular Insights into Agrifood Waste Valorization: From By-Products to Sustainable Resources)

39 pages, 1054 KB

Open AccessReview

Regulating Glucose Metabolism Enzymes for Osteoporosis Therapy: Current and Future Approaches

by Ziwen Zhang, Shuo Tian, Qian Li, Xiuwei Du, Linhui Wang, Na Li, Feng Zhao and Yanqiu Liu

Int. J. Mol. Sci. 2026, 27(10), 4536; https://doi.org/10.3390/ijms27104536 (registering DOI) - 18 May 2026

Abstract

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, microarchitectural deterioration, and an increased risk of fracture. Its pathogenesis is closely associated with disturbances in energy metabolism, particularly glucose metabolic reprogramming in bone cells. Under osteoporotic conditions, the balance between osteoblasts [...] Read more.

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, microarchitectural deterioration, and an increased risk of fracture. Its pathogenesis is closely associated with disturbances in energy metabolism, particularly glucose metabolic reprogramming in bone cells. Under osteoporotic conditions, the balance between osteoblasts and osteoclasts is disrupted, accompanied by impaired oxidative phosphorylation, dysregulated glycolysis, and reduced tricarboxylic acid cycle efficiency, ultimately leading to mitochondrial dysfunction. These metabolic alterations result in an insufficient energy supply and accelerate bone loss. Accordingly, the modulation of key enzymes involved in glucose metabolism has emerged as a promising therapeutic strategy. Strategies include the use of natural compounds, traditional Chinese medicine formulas, and specific inhibitors to modulate glucose metabolism processes and related pathways, thereby restoring cellular energy homeostasis and bone remodeling balance. This review summarizes pharmacological agents regulating glucose metabolism and proposes a hierarchical framework for therapeutic prioritization: first, inhibiting pathological glycolysis in osteoclasts (particularly via LDHA and PKM2). Second, restoring oxidative phosphorylation in osteoblasts (e.g., via COX I–V or ATP synthase). And third, employing multi-target traditional Chinese medicine formulas as complementary strategies. By establishing this cell-type-specific and pathway-specific hierarchy, the review aims to provide a theoretical basis for future research on metabolic interventions in bone diseases. Full article

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

20 pages, 4710 KB

Open AccessArticle

Deciphering the Diagnostic and Natural Therapeutic Implications of Necrosis by Sodium Overload and NK Signatures in Endometriosis Patients

by Juan Du and Zili Lv

Int. J. Mol. Sci. 2026, 27(10), 4535; https://doi.org/10.3390/ijms27104535 (registering DOI) - 18 May 2026

Abstract

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell [...] Read more.

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell activation by increasing cytotoxicity and the inflammatory response in the EMT microenvironment. By integrating three bulk datasets to compare endometrium tissues between endometriosis patients and normal controls and the NESCO gene list from a public database, we identified NK- and NESCO (NN)-associated hub genes via integrative bioinformatic analyses utilizing Limma, WGCNA, CIBERSORT and machine learning frameworks. The diagnostic performance of NN-associated hub genes was evaluated across the three aforementioned datasets and two independent validation sets. Furthermore, their molecular and immune features were estimated at the bulk and single-cell transcriptomic levels. In addition, endometriosis patients were classified into two novel molecular subgroups based on consensus clustering of NN. Finally, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and molecular docking were used to identify compounds in Chinese traditional medicine (CTM) that can target NN-associated hub genes for endometriosis treatment. FABP4 and SLC2A1 can be considered NN-associated hub genes that are involved in EMT pathogenesis, and natural compounds including the CTM GuiZhiFuLingWan (GZFLW) can be considered therapeutic agents for EMT treatment as they target FABP4 and SLC2A1. Our study is the first to reveal the diagnostic and druggable roles of NESCO and NK cells, the corresponding molecular and immune features of NN-associated hub genes, and the therapeutic potential of GZFLW. Full article

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

► Show Figures

Figure 1

15 pages, 823 KB

Open AccessArticle

Comparative Biochemical and Aroma Profiling of Three Dried Chinese Mulberry (Morus spp.) Genotypes

by Junrong Huang, Mesut Ada, Doğan Ergün, Müjgan Güney, Salih Kafkas, Nesibe Ebru Kafkas and Wen Yang

Int. J. Mol. Sci. 2026, 27(10), 4534; https://doi.org/10.3390/ijms27104534 (registering DOI) - 18 May 2026

Abstract

This study aimed to evaluate genotype-dependent variation in biochemical composition, antioxidant capacity, and aroma profiles of dried Chinese mulberry (Morus spp.) genotypes. Three cultivars, Lvmeiren (green), Zhenzhubai (white), and Yunsang No 2 (red), were analyzed. Organic acids and sugars were determined using [...] Read more.

This study aimed to evaluate genotype-dependent variation in biochemical composition, antioxidant capacity, and aroma profiles of dried Chinese mulberry (Morus spp.) genotypes. Three cultivars, Lvmeiren (green), Zhenzhubai (white), and Yunsang No 2 (red), were analyzed. Organic acids and sugars were determined using HPLC, while total phenolic content, antioxidant capacity (DPPH and FRAP), and total anthocyanins were quantified using spectrophotometric methods. Volatile compounds were analyzed by HS-SPME/GC–MS. Significant differences were observed among genotypes for all measured parameters. Among the studied genotypes, Yunsang No 2 exhibited the highest total phenolic content (379.59 mg GAE g⁻¹ DW), FRAP value (21.51 μmol g⁻¹ DW), and anthocyanin content (37.1 mg L⁻¹). In contrast, Lvmeiren was characterized by markedly higher sucrose (22.57%) and succinic acid (3.69%) contents. Zhenzhubai exhibited the highest glucose (25.82%) and fructose (32.65%) contents, together with elevated citric (2.58%) and malic acid (2.93%) levels. Yunsang No 2 showed markedly higher total phenolics, anthocyanins, and antioxidant capacity, indicating superior nutraceutical potential. Volatile compound analysis revealed aldehydes and alcohols as dominant groups in Lvmeiren and Zhenzhubai, while acids were predominant in Yunsang No 2. Multivariate analyses (PCA and hierarchical clustering) clearly separated genotypes based on biochemical and antioxidant traits. These findings demonstrate that genotype plays a critical role in determining the nutritional quality and aroma profile of dried mulberries and provide valuable insights for breeding, cultivar selection, and functional food applications. Full article

(This article belongs to the Special Issue Methodological Advances in Phytochemical Analysis)

14 pages, 1739 KB

Open AccessArticle

SYTL4 May Serve as a New Predictive Biomarker for Survival and Trastuzumab Treatment Responsiveness in HER2-Positive Breast Cancer

by Pawel Kordowitzki

Int. J. Mol. Sci. 2026, 27(10), 4533; https://doi.org/10.3390/ijms27104533 (registering DOI) - 18 May 2026

Abstract

Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for [...] Read more.

Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for patients with breast cancer. Breast cancer transcriptomic datasets were retrieved from the Gene Expression Omnibus and processed through standardized normalization procedures. Mutation-driven regulation of SYTL4 expression, treatment response to trastuzumab, cancer hallmark enrichment, and survival associations were evaluated using established bioinformatic tools and enrichment analysis based on integrated cancer hallmark gene sets. Additionally, DNA methylation profiles were analyzed. Herein, it is shown that SYTL4 mRNA expression is significantly (p = 2.01 × 10⁻⁴) diminished in breast cancer bearing BRCA1 mutations, suggesting a mechanistic interplay between BRCA1-driven genomic instability and SYTL4-regulated signaling cascades. Kaplan–Meier survival analysis demonstrated that elevated SYTL4 mRNA expression is significantly associated with improved overall survival in HER2-positive breast cancer patients (HR = 0.72; p = 0.034). Consistently, SYTL4 expression was significantly higher in patients who responded to trastuzumab therapy, supporting its potential as a biomarker of therapeutic response. Epigenetic analysis further revealed significant differential DNA methylation of SYTL4 between tumor and unaffected control tissues (p < 2.2 × 10⁻¹⁶), with region-specific hypomethylation in tumor regulatory regions. KEGG pathway and cancer hallmark enrichment analyses indicated that genes with prominent methylation changes are involved in cytokine signaling, growth factor pathways, and extracellular matrix remodeling, with the strongest associations observed for hallmarks related to genome instability, replicative immortality, resisting cell death, and metabolic reprogramming. In summary, we present that the gene SYTL4 is a prospective biomarker for survival and trastuzumab treatment responsiveness. Our observations posit that SYTL4 expression may signify a biological milieu conducive to sustained HER2 reliance and amplified therapeutic vulnerability. Full article

(This article belongs to the Special Issue Advances in Molecular Research on Cancer Treatments: Apoptosis, Autophagy, and Drug Selection)

► Show Figures

Figure 1

14 pages, 932 KB

Open AccessArticle

Role of the IRE1α-XBP1 Axis in IgE-Dependent Activation of Mast Cells

by Hiroto Kouda, Kazuki Nagata, Riu Saito and Chiharu Nishiyama

Int. J. Mol. Sci. 2026, 27(10), 4532; https://doi.org/10.3390/ijms27104532 (registering DOI) - 18 May 2026

Abstract

The IRE1α-XBP1 axis is the most conserved of the three major unfolded protein response (UPR) branches triggered by the endoplasmic reticulum (ER) stress. Although the transcription factor XBP1 is involved in the development and function of several hematopoietic lineages, its role in the [...] Read more.

The IRE1α-XBP1 axis is the most conserved of the three major unfolded protein response (UPR) branches triggered by the endoplasmic reticulum (ER) stress. Although the transcription factor XBP1 is involved in the development and function of several hematopoietic lineages, its role in the activation of mast cells (MCs), which are critical in allergic responses, remains largely unknown. We identified salicylaldehyde, which suppresses IRE1α nuclease activity that is essential for XBP1 production, as an inhibitor of MC activation in our previous screening; therefore, we herein investigated the effects of additional IRE1α inhibitors, 3-methyl-6-bromo-salichylaldehyde (MBSA) and KIRA6, targeting the nuclease domain and kinase domain, respectively, on MC activation. MBSA and KIRA6 suppressed IgE-dependent degranulation of bone marrow-derived MCs (BMMCs) but did not inhibit Ca²⁺ ionophore- or compound48/80-induced degranulation. Treatments with inhibitors of two other branches of UPR, the PERK and ATF6 pathways, did not affect the IgE-induced activation of BMMCs. The intraperitoneal administration of MBSA or KIRA6 significantly suppressed IgE-induced passive anaphylaxis in mice. Furthermore, to examine the effects of XBP1, siRNA-mediated knockdown was performed. The results obtained confirmed that Xbp1 siRNA introduction reduced the IgE-dependent degranulation of BMMCs in parallel with the knockdown level of Xbp1 mRNA. Therefore, the IRE1α-XBP1 axis plays a significant role in IgE-dependent and MC-mediated allergic responses and is considered to be a therapeutic target of allergic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma: 4th Edition)

► Show Figures

Graphical abstract

27 pages, 741 KB

Open AccessReview

Integrating Structures and Biology: Cellular and Molecular Interactions with Functionally Graded Spinal Cage Designs

by Yuen Ho Cheng, Amy Libing Fu, Jessica Gaff, Gianluca Vadala, Amit Jain and Javad Tavakoli

Int. J. Mol. Sci. 2026, 27(10), 4531; https://doi.org/10.3390/ijms27104531 (registering DOI) - 18 May 2026

Abstract

Interbody fusion cages are widely used to restore spinal stability, yet conventional designs often exhibit mechanical mismatch and limited biological integration. Functionally graded spinal cages incorporate spatial variations in composition and structure to better align mechanical properties with the surrounding bone environment. Although [...] Read more.

Interbody fusion cages are widely used to restore spinal stability, yet conventional designs often exhibit mechanical mismatch and limited biological integration. Functionally graded spinal cages incorporate spatial variations in composition and structure to better align mechanical properties with the surrounding bone environment. Although these designs have been extensively studied from an engineering perspective, their biological implications remain less clearly defined. This review examines how graded material composition, surface characteristics, porosity, and lattice architecture are associated with cellular and molecular responses relevant to bone regeneration. Reported biological responses include protein adsorption, immune modulation, angiogenesis, and osteogenic differentiation. Evidence from orthopaedic implants and tissue engineering systems suggests that such design features may influence mechanobiological pathways; however, direct experimental validation in spinal applications remains limited. Previous reviews primarily focus on material properties or mechanical performance of functionally graded spinal cages. This review presents a structured design-to-biology perspective linking graded implant features with biological responses relevant to spinal fusion. By integrating findings across biomaterials, mechanobiology, and implant design, this review presents a structured design-to-biology perspective and highlights current evidence, translational limitations, and key knowledge gaps in the field. Functionally graded spinal cages represent a promising but still evolving strategy, and further spine-specific mechanobiological and clinical studies are required to establish their impact on fusion outcomes. Full article

(This article belongs to the Special Issue Emerging Technologies in Musculoskeletal Research: From Molecular Mechanisms to Translational Innovation)

► Show Figures

Graphical abstract

21 pages, 3201 KB

Open AccessArticle

Optogenetic Inhibition of Striatal Parvalbuminergic Interneurons Unmasks Impaired GABA and Adenosine Signaling in DYT1 Knock-In Mice

by Jakob Marx, Susen Becker, Lisa Höfert, Ina Hochheim, Christin Helmschrodt, Jan Dreßler, Angelika Richter and Anja Schulz

Int. J. Mol. Sci. 2026, 27(10), 4530; https://doi.org/10.3390/ijms27104530 (registering DOI) - 18 May 2026

Abstract

Neurochemical imbalances in the striatum are thought to contribute to the pathophysiology of DYT1 dystonia (TOR1A), a severe movement disorder. Parvalbumin-positive GABAergic fast-spiking interneurons (PV+ FSI) exert a powerful inhibition within the striatal microcircuitry. To elucidate the impact of PV+ FSI on striatal [...] Read more.

Neurochemical imbalances in the striatum are thought to contribute to the pathophysiology of DYT1 dystonia (TOR1A), a severe movement disorder. Parvalbumin-positive GABAergic fast-spiking interneurons (PV+ FSI) exert a powerful inhibition within the striatal microcircuitry. To elucidate the impact of PV+ FSI on striatal neurotransmitter dynamics in a DYT1 knock-in (KI) mouse model, we combined optogenetic inhibition of PV+ FSI with in vivo microdialysis (optodialysis) and LC-MS/MS analysis. Dialysates were collected across baseline (light off), stimulation (light on, 595 nm), and post-stimulation (light off) periods. Basal extracellular concentrations of several analytes, including GABA, dopamine, and adenosine, showed no significant differences between wild-type (WT) and DYT1 KI mice. In WT mice, PV+ FSI inhibition decreased GABA and adenosine levels. In contrast, DYT1 KI mice showed no change in GABA and only a delayed reduction in adenosine post-stimulation. Dopamine, choline, or 5-HIAA were largely unaffected by optogenetic inhibition, with the exception of a genotype-specific reduction of 5-HIAA in the post-stimulation period. These findings suggest impaired inhibitory and neuromodulatory control in the DYT1 KI mice, potentially reflecting compensatory circuit adaptations. The results provide novel insights into striatal microcircuit function in DYT1 dystonia, establish a basis for exploring circuit-level alterations in other movement disorders, and may inform future therapeutic strategies. Full article

(This article belongs to the Section Molecular Neurobiology)

► Show Figures

Figure 1

52 pages, 1668 KB

Open AccessReview

Review of Antimicrobial Properties of Carbon Nanomaterials

by Lev R. Sizov, Dmitriy A. Serov, Valeriy A. Kozlov, Valery A. Karpov, Fatikh M. Yanbaev and Sergey V. Gudkov

Int. J. Mol. Sci. 2026, 27(10), 4529; https://doi.org/10.3390/ijms27104529 (registering DOI) - 18 May 2026

Abstract

In various areas of human activity, there is a need for new antimicrobial agents that are minimally hazardous to humans and the environment while remaining effective against multidrug-resistant microorganisms. The use of nanomaterials, particularly carbon-based ones, for this purpose is attracting growing interest. [...] Read more.

In various areas of human activity, there is a need for new antimicrobial agents that are minimally hazardous to humans and the environment while remaining effective against multidrug-resistant microorganisms. The use of nanomaterials, particularly carbon-based ones, for this purpose is attracting growing interest. This review presents a quantitative analysis, based on published data, of the antibacterial and antifungal activity of various carbon nanomaterials, focusing on fullerenes, nanodiamonds, graphene oxide, carbon nanotubes, and carbon dots. Their antimicrobial activity is compared both among themselves and with other antimicrobial agents; the effects of their physicochemical properties, functionalization, and photodynamic activity on this activity are also examined. Full article

(This article belongs to the Special Issue Advanced Research on Antimicrobial Nanomaterials)

16 pages, 602 KB

Open AccessReview

A Signaling-Threshold Framework for Human Tooth Agenesis: Integrating Molecular Genetics with Developmental Field Theory

by Anna Ewa Kuc, Paulina Kuc, Natalia Kuc, Magdalena Sulewska, Marzena Tylicka and Michał Sarul

Int. J. Mol. Sci. 2026, 27(10), 4528; https://doi.org/10.3390/ijms27104528 (registering DOI) - 18 May 2026

Abstract

Tooth agenesis is a common developmental anomaly of the human dentition, ranging from hypodontia to oligodontia, yet its marked phenotypic variability remains insufficiently explained. This review synthesizes developmental and molecular evidence on epithelial–mesenchymal interactions during early odontogenesis and proposes a signaling-threshold framework for [...] Read more.

Tooth agenesis is a common developmental anomaly of the human dentition, ranging from hypodontia to oligodontia, yet its marked phenotypic variability remains insufficiently explained. This review synthesizes developmental and molecular evidence on epithelial–mesenchymal interactions during early odontogenesis and proposes a signaling-threshold framework for human tooth agenesis. We focus on the coordinated roles of Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (SHH) pathways and on recurrent disease-associated genes, including MSX1, PAX9, WNT10A, and AXIN2, as quantitative modulators of pathway activity rather than binary determinants of tooth identity. Within this framework, successful tooth initiation may depend on whether integrated signaling output exceeds a field-specific activation threshold within spatially graded developmental regions of the dental arch. Differences in signaling amplitude, duration, and transcriptional responsiveness may therefore account for distal tooth susceptibility, variable penetrance, arch asymmetry, and the broad clinical spectrum from mild hypodontia to severe oligodontia. By integrating molecular genetics with developmental field theory, this model provides a testable systems-level explanation for selective tooth absence and highlights priority directions for future functional and genotype–phenotype studies. Full article

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

59 pages, 1348 KB

Open AccessReview

Current Understanding of Probiotic Strains and Immune Function: From Gut Microbiota to Systemic Immunity

by Maciej Piotr Szota, Katarzyna Napiórkowska-Baran, Aleksandra Wojtkiewicz, Lidia Wydeheft, Adam Wawrzeńczyk, Józef Sławatycki, Paweł Treichel, Ewa Alska, Barbara Zyśk and Krzysztof Pałgan

Int. J. Mol. Sci. 2026, 27(10), 4527; https://doi.org/10.3390/ijms27104527 (registering DOI) - 18 May 2026

Abstract

Growing evidence indicates that the gut microbiota is a central regulator of systemic immunity, acting through epithelial barrier integrity, microbial metabolites, and bidirectional signaling with innate and adaptive immune cells. Within this framework, probiotics have attracted substantial interest as tools for immune modulation; [...] Read more.

Growing evidence indicates that the gut microbiota is a central regulator of systemic immunity, acting through epithelial barrier integrity, microbial metabolites, and bidirectional signaling with innate and adaptive immune cells. Within this framework, probiotics have attracted substantial interest as tools for immune modulation; however, their effects are not uniform and should not be generalized across species or formulations. This review synthesizes current evidence on the gut microbiota–immune axis and examines how defined probiotic strains influence immune homeostasis, inflammation, and clinical outcomes. Particular emphasis is placed on strain-specific effects among lactic acid bacteria, bifidobacteria, yeast probiotics, and emerging nontraditional candidates, with attention to mechanisms involving cytokine signaling, regulatory T-cell induction, nuclear factor kappa B (NF-κB) modulation, toll-like receptor (TLR) pathways, short-chain fatty acids (SCFAs), tryptophan metabolites, and bile-acid-dependent signaling. The available literature indicates that the most meaningful immunological effects arise from precisely characterized strains acting in specific host contexts, whereas inconsistent trial design, small sample sizes, variable dosing, and poor strain resolution continue to limit translation. Overall, current data support a shift from generic probiotic use toward mechanism-based, strain-specific, and increasingly personalized strategies for immune modulation. Full article

(This article belongs to the Special Issue Latest Research on Probiotics: Molecular Mechanisms and Health Applications)

31 pages, 8149 KB

Open AccessArticle

Amplicon-Based Profiling of Fungal Communities Associated with Scots Pine Bark Beetles: Selective Antagonism and Monoterpene Tolerance

by Arunabha Khara, Sandipan Banerjee, Amrita Chakraborty, Jakub Dušek, Jiří Synek and Amit Roy

Int. J. Mol. Sci. 2026, 27(10), 4526; https://doi.org/10.3390/ijms27104526 (registering DOI) - 18 May 2026

Abstract

Bark beetle–fungus associations are essential for nutrition, detoxification, and host colonisation, but their composition and function vary across developmental stages and environmental contexts. Hence, we characterised the fungal communities associated with two pine-feeding bark beetles, Ips sexdentatus (ISX) and Ips. acuminatus (IAC), across [...] Read more.

Bark beetle–fungus associations are essential for nutrition, detoxification, and host colonisation, but their composition and function vary across developmental stages and environmental contexts. Hence, we characterised the fungal communities associated with two pine-feeding bark beetles, Ips sexdentatus (ISX) and Ips. acuminatus (IAC), across developmental stages and compared wild-collected and laboratory-bred populations using ITS2 amplicon sequencing. Both beetle species maintained a stable core mycobiome dominated by Kuraishia, Ogataea, Ophiostoma, Graphilbum, and Cyberlindnera. These taxa have been earlier reported to be associated with nutrient provisioning, detoxification of host secondary metabolites, and chemical signalling. Adult beetles showed species-specific community differences, whereas wild-collected beetles, particularly IAC, harboured higher fungal diversity than laboratory populations, indicating a strong environmental effect. Beetles shared more fungal taxa with control wood than with gallery wood, suggesting possible fungal acquisition during feeding and concurrent restructuring of the wood mycobiome during infestation. Monoterpene bioassays with selected yeast symbionts showed differential growth responses to α-pinene, 3-carene, and terpinolene, and their mixture, with the mixture producing stronger inhibition than individual compounds. These yeast symbionts further displayed selective antagonistic activity in vitro against selected filamentous fungi, including entomopathogenic taxa, along with detectable lytic and digestive enzyme activities. Together, our findings highlight a link between community structure, predicted functions, and observed interaction phenotypes, providing a strong basis for future mechanistic studies of beetle–fungus–conifer interactions. Full article

(This article belongs to the Special Issue Molecular Insights into Microbial Dynamics in Agroforestry for Resilience and Climate Adaptation)

► Show Figures

Graphical abstract

20 pages, 831 KB

Open AccessReview

The Double-Edged Sword: How Radiotherapy Shapes the Tumor Immune Microenvironment to Modulate Responses to Checkpoint Inhibitors

by Chen-Hsuan Chiang, Hui-Wen Chan and Hui-Yen Chuang

Int. J. Mol. Sci. 2026, 27(10), 4525; https://doi.org/10.3390/ijms27104525 (registering DOI) - 18 May 2026

Abstract

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of [...] Read more.

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn “cold” tumors into “hot” ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology. Full article

(This article belongs to the Special Issue Cancer Immunotherapy on Checkpoint Inhibitors: Future Directions)

23 pages, 1584 KB

Open AccessArticle

Phosphonamidates Integrating Sterically Hindered Phenols with Membrane-Active Cations: A Redox-Activated Approach to Antimicrobial Agents

by Elmira Gibadullina, Adel Shakirov, Margarita Neganova, Yulia Aleksandrova, Alexandra Voloshina, Anna Lyubina, Anastasiya Sapunova, Anna Strelnik, Kamil Ivshin, Assel Shuragaziyeva, Altynkul Toibazarova, Banu Diyarova, Anipa Tapalova, Nurbol Appazov and Alexander Burilov

Int. J. Mol. Sci. 2026, 27(10), 4524; https://doi.org/10.3390/ijms27104524 (registering DOI) - 18 May 2026

Abstract

A strategy to create highly effective antimicrobial agents was proposed based on the conjugation of three functional components: a cationic quaternary ammonium salt (QAS) that exerts a membrane-disrupting effect and promotes selective accumulation on bacterial surfaces; a phosphonamidate linker for controlled activation; and [...] Read more.

A strategy to create highly effective antimicrobial agents was proposed based on the conjugation of three functional components: a cationic quaternary ammonium salt (QAS) that exerts a membrane-disrupting effect and promotes selective accumulation on bacterial surfaces; a phosphonamidate linker for controlled activation; and a sterically hindered phenol (SHP) fragment as a potential redox component. This approach enabled the preparation of 40 target phosphonamidate–SHP/QAS hybrids in high yields (88–98%). Evaluation of their antimicrobial activity against major pathogens and methicillin-resistant Staphylococcus aureus (MRSA) revealed high potency against Gram-positive bacteria. The lead compounds achieved minimum inhibitory concentration (MIC) values of 0.7–2.8 μM, which is up to 10 times lower than that of the reference drug, norfloxacin. Mechanistic studies confirmed that these hybrids disrupt the bacterial membrane. In addition, an increase in intracellular ROS levels was observed for the most active compound. The SHP/QAS hybrids retained high activity against S. aureus ATCC 209P after 17 passages and showed low cytotoxicity (SI = 62–92) and negligible hemolysis. These properties indicate that this approach may offer a useful strategy for developing antibacterial agents with a potentially lower risk of inducing conventional resistance mechanisms. Full article

(This article belongs to the Special Issue Interactions Between Microbes and Hosts: Physiology, Pathology and Treatment—Second Edition)

► Show Figures

Graphical abstract

14 pages, 7035 KB

Open AccessArticle

Minimization of Cancellation Effect with Nisin During Bipolar Nanosecond Electrochemotherapy

by Veronika Malyško, Aušra Nemeikaitė-Čėnienė, Olga Michel, Arnoldas Morozas, Zofia Łapińska, Eglė Mickevičiūtė-Zinkuvienė, Paulina Malakauskaitė, Augustinas Želvys, Barbora Lekešytė, Justinas Ivaška, Julita Kulbacka and Vitalij Novickij

Int. J. Mol. Sci. 2026, 27(10), 4523; https://doi.org/10.3390/ijms27104523 (registering DOI) - 18 May 2026

Abstract

Bipolar cancellation (BPC) is an efficiency-limiting phenomenon in bipolar nanosecond pulsed electric field (nsPEF) exposures, in which the second, opposite-polarity phase reduces or partially reverses the electroporation induced by the first phase. Nisin, a cationic antibiotic peptide, has been reported to interact with [...] Read more.

Bipolar cancellation (BPC) is an efficiency-limiting phenomenon in bipolar nanosecond pulsed electric field (nsPEF) exposures, in which the second, opposite-polarity phase reduces or partially reverses the electroporation induced by the first phase. Nisin, a cationic antibiotic peptide, has been reported to interact with lipid membranes in bacterial systems and artificial bilayer models, where it may contribute to membrane destabilization and increased permeability during pulsed electric field exposure. This study investigated whether nisin may enhance the efficacy of bleomycin electrochemotherapy (ECT) in the presence of bipolar nanosecond pulses, which are typically associated with pronounced BPC effects. Pulsed electric field (PEF) parameters and drug concentrations were selected based on preliminary viability and Yo-Pro-1 uptake experiments in CLS-354 human squamous cell carcinoma cells. To evaluate the effect of nisin, cell viability and membrane permeabilization were assessed following exposure to 300 ns pulses across a range of bipolar PEF protocols, with or without nisin, while identical unipolar pulses were used for comparison. Nisin (50 µg/mL) increased membrane permeabilization across the tested range of field amplitudes (9–15 kV/cm) and burst repetition frequencies (0.1–1.66 MHz). The presence of nisin was also associated with increased efficacy of bleomycin-based ECT under both unipolar and symmetrical bipolar PEF conditions. Under the optimized parameters tested (13 kV/cm; 150 pulses of 300 ns at 1.66 MHz), bipolar nsPEFs in combination with nisin reached levels of efficacy comparable to those observed with unipolar waveforms, suggesting a potential attenuation of bipolar cancellation effects. Full article

(This article belongs to the Special Issue Application of Pulsed Electric Fields in Cancer Therapy)

► Show Figures

Figure 1

23 pages, 606 KB

Open AccessArticle

Integrating Molecular Biology and Cryptography: A DNA and RNA-Based Framework for Secure Data Encryption

by Muhammad Naeem Akhtar, Jawad Hussain Awan, Abdul Mateen Shahzaib Asad and Min Young Kim

Int. J. Mol. Sci. 2026, 27(10), 4522; https://doi.org/10.3390/ijms27104522 (registering DOI) - 18 May 2026

Abstract

The rapid growth of digital communication and large-scale data exchange has increased the demand for advanced cryptographic techniques capable of resisting emerging computational threats. Conventional encryption methods primarily rely on mathematical complexity, which may become vulnerable with the advancement of high-performance computing and [...] Read more.

The rapid growth of digital communication and large-scale data exchange has increased the demand for advanced cryptographic techniques capable of resisting emerging computational threats. Conventional encryption methods primarily rely on mathematical complexity, which may become vulnerable with the advancement of high-performance computing and future quantum technologies. Biological molecules such as deoxyribonucleic acid (DNA) and RiboNucleic Acid (RNA) provide unique properties, including extremely high storage density, massive parallelism, and complex nucleotide structures that can inspire novel cryptographic mechanisms. This study proposes a bio-inspired cryptographic framework that integrates DNA encoding and RNA-based transformations to enhance data security. In the proposed framework, digital information is first converted into binary format and mapped to nucleotide sequences using a predefined encoding scheme. The encryption process incorporates multiple molecular transformations, including complementary base pairing, sequence permutation, and transcription-inspired DNA-to-RNA conversion to generate a highly randomized ciphertext. Decryption reverses these transformations to reconstruct the original plaintext. Security evaluation demonstrates that the proposed framework produces high entropy outputs, a substantially large key space, and enhanced resistance to statistical and brute-force attacks. The results indicate that DNA and RNA-inspired cryptographic systems can substantially enhance encryption complexity while maintaining reliable data recovery. This research highlights the potential of molecular cryptography as a promising interdisciplinary approach for future secure communication and biological data storage systems. Full article

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

25 pages, 964 KB

Open AccessReview

Growth Hormone and Brain Regeneration: Evidence from Clinical Studies in Dementia, Traumatic Brain Injury, and Stroke: A Systematic Review

by Vittorio Emanuele Bianchi, Lily Castellar Visbal and Jesús Devesa

Int. J. Mol. Sci. 2026, 27(10), 4521; https://doi.org/10.3390/ijms27104521 (registering DOI) - 18 May 2026

Abstract

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy [...] Read more.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer’s disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: “GH and dementia,” “GH and Alzheimer’s disease,” “GH and TBI,” and “GH and stroke.” Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer’s disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

27 pages, 1156 KB

Open AccessReview

Biomolecular Condensates in Combined and Recurrent Plant Stresses: Integrating Phase Separation, Signal Prioritization, and Cross-Stress Memory

by Sajid Ali and Yong-Sun Moon

Int. J. Mol. Sci. 2026, 27(10), 4520; https://doi.org/10.3390/ijms27104520 (registering DOI) - 18 May 2026

Abstract

Plants frequently encounter overlapping, sequential, and recurrent stresses, but the cellular mechanisms that organize responses to these complex conditions remain incompletely understood. Biomolecular condensates are membrane-less assemblies formed through phase separation and multivalent molecular interactions, and they can regulate RNA metabolism, protein sequestration, [...] Read more.

Plants frequently encounter overlapping, sequential, and recurrent stresses, but the cellular mechanisms that organize responses to these complex conditions remain incompletely understood. Biomolecular condensates are membrane-less assemblies formed through phase separation and multivalent molecular interactions, and they can regulate RNA metabolism, protein sequestration, signaling specificity, transcriptional control, and stress recovery. This review evaluates the hypothesis that plant condensates may contribute to the organization of combined and recurrent stress responses by modulating molecular accessibility, transcript fate, proteostasis, and regulatory crosstalk. We synthesize current knowledge on stress granules, processing bodies, nuclear condensates, plastid-associated condensate-like assemblies, and other stress-responsive compartments, with emphasis on their possible roles in signal filtering, RNA triage, and recovery-associated reprogramming. We also distinguish established evidence from emerging hypotheses, particularly regarding condensate-mediated signal prioritization and stress memory. Current data support condensates as rapid stress-responsive organizers, but direct evidence for their persistence after recovery or their causal roles under simultaneous multi-stress conditions remains limited. By integrating phase separation biology with plant multi-stress physiology, this review proposes a testable conceptual framework and identifies methodological priorities for future studies in plant stress resilience and crop improvement. Full article

(This article belongs to the Section Molecular Plant Sciences)

30 pages, 4805 KB

Open AccessArticle

Spatiotemporal APLNR Expression Dynamics During Oligodendroglial Remodeling of the Corpus Callosum in the Cuprizone Model

by Lyubomir Gaydarski, Kristina Petrova, Nikola Stamenov, Alexandar Iliev, Stancho Stanchev, Pavel Rashev, Despina Pupaki, Milena Mourdjeva, Ivanka Kostadinova and Boycho Landzhov

Int. J. Mol. Sci. 2026, 27(10), 4519; https://doi.org/10.3390/ijms27104519 (registering DOI) - 18 May 2026

Abstract

Demyelinating disorders such as multiple sclerosis are characterized by oligodendrocyte loss and insufficient remyelination. The cuprizone model provides a well-established experimental system for studying these processes. The apelinergic system, including the apelin receptor (APLNR), has been implicated in neuroprotection and central nervous system [...] Read more.

Demyelinating disorders such as multiple sclerosis are characterized by oligodendrocyte loss and insufficient remyelination. The cuprizone model provides a well-established experimental system for studying these processes. The apelinergic system, including the apelin receptor (APLNR), has been implicated in neuroprotection and central nervous system homeostasis. However, its role in white matter demyelination and repair remains incompletely understood. This study aimed to characterize the spatial and temporal dynamics of APLNR expression in relation to oligodendrocyte lineage cells in the corpus callosum (CC) during demyelination and remyelination. Demyelination was induced in 8-week-old C57BL/6 mice by 0.2% cuprizone supplementation in their drinking water for 5 weeks, followed by 5 weeks remyelination phase after toxin withdrawal. Histological assessment using Luxol Fast Blue/Cresyl violet staining was performed to evaluate structural changes in the CC. Immunohistochemistry and confocal microscopy were used to analyze APLNR expression, GST-π⁺ cells, and NG2⁺ cells, including their spatial distribution and co-localization. Quantitative analyses and correlation tests were conducted to assess relationships between cellular markers and CC area. Demyelination resulted in significant reduction in CC area and a marked decrease in GST-π⁺ cells, accompanied by a robust increase in NG2⁺ cells, while remyelination led to partial structural and cellular recovery. APLNR expression increased progressively from control to demyelination and further during remyelination, exhibiting pronounced regional heterogeneity with higher levels in lateral CC regions. Confocal analysis demonstrated increasing co-localization of APLNR with NG2⁺ cells, particularly during remyelination. Correlation analyses identified GST-π⁺ cell density as the strongest predictor of CC area, whereas APLNR showed phase-dependent associations, including a positive correlation with GST-π⁺ cells during remyelination and a negative relationship with NG2⁺ cells during demyelination. APLNR expression is dynamically regulated during cuprizone-induced demyelination and remyelination and is closely associated with oligodendrocyte lineage cell responses. Its increased expression and enhanced co-localization with NG2⁺ cells during remyelination suggest a potential role in endogenous repair processes. However, as the findings are based on descriptive analyses, further functional studies are required to determine the mechanistic contribution of APLNR signaling and its potential as a therapeutic target in demyelinating diseases. Full article

(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)

► Show Figures

Figure 1

Journal Description

International Journal of Molecular Sciences

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI