International Journal of Molecular Sciences

16 pages, 2003 KB

Open AccessArticle

Therapeutic Anti-Fibrotic Effects of a Dual Hyaluronic Acid Hybrid Complex in Bleomycin-Induced Dermal Fibrosis and UVB-Irradiated Human Skin

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

Int. J. Mol. Sci. 2026, 27(7), 3038; https://doi.org/10.3390/ijms27073038 (registering DOI) - 26 Mar 2026

Abstract

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has [...] Read more.

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has demonstrated regenerative and antioxidant properties, but its anti-fibrotic effects have not been fully explored. This study investigated the anti-fibrotic potential of DHC using a bleomycin-induced murine dermal fibrosis model and a UVB-irradiated ex vivo human skin model. In C57BL/6 mice, dermal fibrosis was induced by daily bleomycin injections for three weeks, followed by intradermal DHC administration. Histological and biomechanical analyses showed that DHC significantly reduced dermal thickness, collagen deposition, and skin hardness compared with untreated fibrotic controls. DHC decreased α-SMA expression and increased MMP1 levels, indicating attenuation of myofibroblast activation and enhanced matrix remodeling. It also reduced macrophage markers (CD68, CD163) and pro-inflammatory cytokines (IL-1β, TNF-α). Furthermore, DHC restored superoxide dismutase (SOD) and catalase (CAT) activity and upregulated NRF2, HO-1, and NQO1 expression in the in vivo model. Similarly, DHC upregulated SOD and CAT activity and reduced pro-inflammatory cytokines (IL-6, TNF-α) in the ex vivo human skin model. These findings suggest that DHC exerts multimodal anti-fibrotic effects through coordinated regulation of fibroblast activation, inflammation, and oxidative stress, supporting its potential as a therapeutic approach for cutaneous fibrosis. Full article

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

► Show Figures

Figure 1

19 pages, 1172 KB

Open AccessArticle

Deciphering Seedling-Stage Salinity Stress Tolerance in Maize Genotypes Through Morpho-Physiological and Ionic Traits

by Pardeep Kumar, Vineeth T. V., Shyam Bir Singh, Mukesh Choudhary, Bhupender Kumar, Anuj Kumar, Sujay Rakshit and Hanuman Sahay Jat

Int. J. Mol. Sci. 2026, 27(7), 3037; https://doi.org/10.3390/ijms27073037 (registering DOI) - 26 Mar 2026

Abstract

Salinity stress impairs maize growth by inducing osmotic stress, pigment degradation, and ionic imbalance, particularly during early seedling development. This study investigated the morpho-physiological and ionic responses of different maize genotypes exposed to increasing salinity levels (control, 3, 6, and 9 dS/m) at [...] Read more.

Salinity stress impairs maize growth by inducing osmotic stress, pigment degradation, and ionic imbalance, particularly during early seedling development. This study investigated the morpho-physiological and ionic responses of different maize genotypes exposed to increasing salinity levels (control, 3, 6, and 9 dS/m) at the seedling stage. Salinity caused a reduction in biomass accumulation (shoot fresh weight and shoot dry weight), plant height, and K⁺/Na⁺ ratio, with pronounced effects under severe stress. Significant genotypic variability was detected for photosynthetic pigments (chlorophyll a, chlorophyll b, total chlorophyll and carotenoids) growth traits, and ionic regulation, indicating diverse physiological adaptation strategies. Stress tolerance indices and multivariate analysis revealed that chlorophyll stability, carotenoid accumulation, and maintenance of ionic homeostasis (K⁺/Na⁺ ratio) were the dominant physiological determinants of salinity tolerance. Additionally, principal component analysis showed a shift from biomass-driven variation under non-stress conditions to pigment- and ion-driven variation under higher salinity. Based on the results, genotypes BML 6 and HKI 163 maintained higher pigment content and improved K⁺/Na⁺ balance, enabling better growth under saline conditions. These findings highlight key physiological traits underlying salinity tolerance and provide insight into early-stage adaptive mechanisms in maize. Full article

(This article belongs to the Topic Plant Responses and Tolerance to Salinity Stress, 2nd Edition)

20 pages, 1582 KB

Open AccessArticle

Cellular Target Engagement and Dissociation Kinetics of Class I-Selective Histone Deacetylase (HDAC) Inhibitors

by Irina Honin, Zora Novakova, Felix Feller, Simon Schneider, Linda Schäker-Hübner, Cyril Barinka and Finn K. Hansen

Int. J. Mol. Sci. 2026, 27(7), 3036; https://doi.org/10.3390/ijms27073036 (registering DOI) - 26 Mar 2026

Abstract

Histone deacetylases (HDACs) 1–3 are key regulators of gene expression and represent important therapeutic targets in cancer, neurodegenerative, and immune disorders. Many potent class I HDAC inhibitors display slow- and tight-binding kinetics, which profoundly influence their efficacy and pharmacodynamics. In particular, their dissociation [...] Read more.

Histone deacetylases (HDACs) 1–3 are key regulators of gene expression and represent important therapeutic targets in cancer, neurodegenerative, and immune disorders. Many potent class I HDAC inhibitors display slow- and tight-binding kinetics, which profoundly influence their efficacy and pharmacodynamics. In particular, their dissociation rate (off-kinetic) is critical, since prolonged target engagement greatly influences drug efficacy in vivo. However, the off-kinetics of HDAC inhibitors are often overlooked in the early stages of drug development. Here, we investigated the dissociation kinetics of tucidinostat, trapoxin A, and TNG260 in comparison to the pan-HDAC inhibitor vorinostat. Using biochemical 100-fold jump dilution assays, NanoBRET assays, and cellular washout experiments, we characterized the dissociation of these compounds from purified proteins and in a cellular context. Tucidinostat showed moderately slow off-kinetics, while the clinical candidate TNG260 demonstrated pronounced tight-binding properties. Trapoxin A displayed remarkable discrepancies between assays, as it showed fast dissociation kinetics in the biochemical assay, but tight-binding properties in a cellular setting. These findings not only address the previously unexplored dissociation kinetics of two clinically relevant inhibitors, but also underscore the importance of comprehensive kinetic profiling of novel HDAC inhibitors in cellular models. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

17 pages, 598 KB

Open AccessReview

Mapping the Extended Pain Pathway: Human Genetic and Multi-Omic Strategies for Next-Generation Analgesics

by Ari-Pekka Koivisto

Int. J. Mol. Sci. 2026, 27(7), 3035; https://doi.org/10.3390/ijms27073035 (registering DOI) - 26 Mar 2026

Abstract

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient [...] Read more.

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

(This article belongs to the Special Issue Pain Pathways Rewired: Moving past Peripheral Ion Channel Strategies)

17 pages, 4312 KB

Open AccessArticle

Reduced GEN1 Expression Is Associated with Elevated DNA Damage and Impaired Proliferation in Endometriosis-Derived Endometrial Organoids

by Berivan Guzelbag, Nazli Ece Gungor, Hadice Karahan, Alireza Maghsoudi and Engin Oral

Int. J. Mol. Sci. 2026, 27(7), 3034; https://doi.org/10.3390/ijms27073034 (registering DOI) - 26 Mar 2026

Abstract

Endometriosis affects approximately 10% of reproductive-age women and is associated with genomic instability; however, the contribution of specific DNA repair deficiencies remains poorly understood. This study investigated the expression and function of GEN1, a Holliday junction resolvase critical for homologous recombination, in [...] Read more.

Endometriosis affects approximately 10% of reproductive-age women and is associated with genomic instability; however, the contribution of specific DNA repair deficiencies remains poorly understood. This study investigated the expression and function of GEN1, a Holliday junction resolvase critical for homologous recombination, in patient-derived endometrial epithelial organoids (EEOs). Endometrial tissue was obtained by pipelle biopsy from women with laparoscopically confirmed endometriosis (n = 3, stage III–IV) and controls without endometriosis (n = 3). GEN1 mRNA and protein expression were reduced in primary endometrial cells from endometriosis patients compared with controls (mRNA: 0.52 ± 0.14 vs. 1.00 ± 0.19, p = 0.05; immunofluorescence intensity: 0.54 ± 0.18 vs. 1.00 ± 0.22, p = 0.05). Patient-derived EEOs from the endometriosis group showed trends toward lower formation efficiency (18.4 ± 5.6% vs. 25.2 ± 6.8%, p = 0.10) and reduced mean diameter (124.6 ± 34.2 vs. 155.8 ± 32.6 µm, p = 0.10). RNA interference (RNAi)-mediated GEN1 knockdown reduced proliferation in both groups, with a more pronounced effect in endometriosis-derived EEOs (49.7% vs. 39.5% reduction, p = 0.05). Endometriosis-derived EEOs exhibited elevated baseline γH2AX (phosphorylated histone H2AX) immunofluorescence compared with controls (2.32 ± 0.44 vs. 1.00 ± 0.28, p = 0.05), indicating increased DNA double-strand break accumulation. Furthermore, GEN1 knockdown directly increased γH2AX intensity in both groups, with endometriosis-derived EEOs showing a greater absolute increase (Δ1.26 vs. Δ0.72). To our knowledge, this study provides the first organoid-based evidence that GEN1 is downregulated in endometriosis and functionally linked to impaired proliferation and elevated DNA damage, suggesting a potential contribution of homologous recombination dysregulation to endometriosis pathogenesis. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

29 pages, 2593 KB

Open AccessArticle

Naproxen and Ibuprofen Exposure Alter the Blood–Testis Barrier in a Novel In Vitro Model

by Krista M. Symosko Crow, In Ki Cho, Robert Clayton Edenfield, Kristen F. Easley, Ana Planinić, Nagham Younis, Elizabeth Waters, James S. McClellan, Amanda Colvin Zielen, Kylie Tager, Carlos Castro, Calvin Simerly, Kyle Orwig, Davor Ježek, Michael Koval and Charles A. Easley IV

Int. J. Mol. Sci. 2026, 27(7), 3033; https://doi.org/10.3390/ijms27073033 (registering DOI) - 26 Mar 2026

Abstract

Semen parameters, including sperm counts, have rapidly declined in men across the globe over the last five decades. Although this decline remains unexplained, lifestyle factors may affect male fertility. Recently, several studies highlighted a potential link between non-steroidal anti-inflammatory drug (NSAID) usage, such [...] Read more.

Semen parameters, including sperm counts, have rapidly declined in men across the globe over the last five decades. Although this decline remains unexplained, lifestyle factors may affect male fertility. Recently, several studies highlighted a potential link between non-steroidal anti-inflammatory drug (NSAID) usage, such as naproxen and ibuprofen, and declining male fertility. However, the mechanisms by which these common analgesics affect male fertility, including their effects on the blood–testis barrier (BTB), remain poorly characterized. Utilizing an in vitro rhesus macaque non-human primate (NHP) BTB model, we demonstrate that serum levels of naproxen and ibuprofen alter the function of BTB. Following short-term naproxen and ibuprofen treatment of NHP primary Sertoli cells, we show that these NSAIDs increase the transepithelial electrical resistance, indicating an overall strengthening of the Sertoli cell junctions. Furthermore, naproxen and ibuprofen treatment alter the expression of genes involved in maintaining the BTB. Specifically, the genes that were significantly expressed in response to ibuprofen exposure were enriched for human phenotypic abnormalities linked to male factor infertility. Together, these results suggest that short-term naproxen and ibuprofen treatment disrupt the function of the BTB by altering the integrity of the Sertoli cell junctions, proposing a potential role of NSAIDs in male factor infertility. Full article

(This article belongs to the Special Issue Sperm Oxidative Stress and Male Infertility)

31 pages, 1506 KB

Open AccessReview

siRNA Nanoparticle Delivery Strategies and Clinical Trial Advances in Tumor Therapy

by Pingjie Wang, Jing Gong, Yilin Xu and Xinhua Xia

Int. J. Mol. Sci. 2026, 27(7), 3032; https://doi.org/10.3390/ijms27073032 - 26 Mar 2026

Abstract

siRNA, as a precise, specific, and highly effective gene-silencing therapy, has been extensively studied. Before reaching tumor cell targets, siRNA formulations must overcome multiple extracellular barriers, including clearance from the bloodstream, membrane impermeability, capture by the mononuclear phagocyte system (MPS), rapid renal excretion, [...] Read more.

siRNA, as a precise, specific, and highly effective gene-silencing therapy, has been extensively studied. Before reaching tumor cell targets, siRNA formulations must overcome multiple extracellular barriers, including clearance from the bloodstream, membrane impermeability, capture by the mononuclear phagocyte system (MPS), rapid renal excretion, endosomal escape, and precise recognition of target cells. These challenges limit siRNA’s clinical application. Consequently, various modifications have been applied to siRNA to enhance transfection efficiency, while researchers continue to pursue improved siRNA-targeting delivery systems. Nanotechnology offers a rational technical approach to address siRNA delivery. Nanoparticles can increase transfection efficiency while exhibiting lower cytotoxicity and reduced off-target effects. Various matrices have been employed to construct nanoparticles for targeted therapeutic delivery. This review briefly discusses siRNA nanoparticle delivery strategies, illustrates examples of various siRNA nanodelivery systems, such as lipid nanoparticles, polymeric siRNA nanoparticles, inorganic nanoparticles, hybrid nanoparticles, and conjugate-siRNA delivery systems, and introduces clinical trials of siRNA-loaded nanoparticles for cancer treatment, which can provide valuable references for further research and clinical application of siRNA nanoparticle delivery systems. Full article

(This article belongs to the Section Molecular Nanoscience)

► Show Figures

Graphical abstract

15 pages, 599 KB

Open AccessReview

SIRT1 in Atherosclerosis: Integrative Control of Vascular Metabolism, Inflammation and Aging

by Yingxuan Chang, Le Li and Hongmei Yue

Int. J. Mol. Sci. 2026, 27(7), 3031; https://doi.org/10.3390/ijms27073031 - 26 Mar 2026

Abstract

Atherosclerosis is a chronic inflammatory and metabolic disease driven by endothelial dysfunction, immune activation, vascular smooth muscle cell remodeling and aging-associated mitochondrial decline. Although lipid lowering remains the cornerstone of therapy, substantial residual inflammatory risk persists, highlighting the need for integrative regulatory targets. [...] Read more.

Atherosclerosis is a chronic inflammatory and metabolic disease driven by endothelial dysfunction, immune activation, vascular smooth muscle cell remodeling and aging-associated mitochondrial decline. Although lipid lowering remains the cornerstone of therapy, substantial residual inflammatory risk persists, highlighting the need for integrative regulatory targets. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, has emerged as a central metabolic sensor linking energy availability to transcriptional control of inflammation, oxidative stress, mitochondrial biogenesis and cellular senescence. Experimental studies across endothelial cells, macrophages and vascular smooth muscle cells consistently demonstrate that SIRT1 activation preserves nitric oxide bioavailability, suppresses ROS-dependent inflammasome signaling, modulates macrophage polarization, inhibits ferroptosis and maintains mitochondrial integrity. These cell-type-specific effects converge to reduce plaque progression and enhance fibrous cap stability in preclinical models. However, SIRT1 activity is hierarchically regulated by AMPK signaling and NAD⁺ availability and is influenced by aging, metabolic dysfunction and environmental stressors, underscoring its context-dependent function. Despite promising mechanistic data, clinical translation remains limited, suggesting that precision modulation strategies may be required. This review synthesizes current evidence and proposes that SIRT1 functions as a metabolic–inflammatory integrator within the atherosclerotic arterial wall, representing a potential but context-sensitive target for future cardiovascular therapies. Full article

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

► Show Figures

Figure 1

24 pages, 3252 KB

Open AccessArticle

Serotonin Modulates Stellate Cell Excitability via 5-HT Receptors and HCN Channels in the Mouse Anteroventral Cochlear Nucleus

by Beytullah Özkaya, Caner Yıldırım, Ender Erdoğan, Mehmet Şerif Aydın and Ramazan Bal

Int. J. Mol. Sci. 2026, 27(7), 3030; https://doi.org/10.3390/ijms27073030 - 26 Mar 2026

Abstract

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in [...] Read more.

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in the mouse anteroventral cochlear nucleus (AVCN) and to determine the underlying ion channel mechanisms. Whole-cell patch-clamp recordings were performed in acute brain slices obtained from postnatal day 12–17 mice. Bath application of serotonin (25 µM) induced membrane depolarization (~5 mV) and increased action potential firing. Pharmacological experiments demonstrated that antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors partially reversed the depolarization and reduced serotonin-induced inward currents, indicating that multiple receptor subtypes contribute to serotonergic excitation. Blockade of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with extracellular Cs⁺ suppressed approximately 95% of the serotonin-induced depolarization and inward current, implicating HCN channel-mediated Ih as a principal ionic mechanism. Serotonin significantly increased Ih amplitude. Analysis of steady-state activation revealed no statistically significant shift in V0.5; however, under near-resting membrane potential conditions, serotonin significantly reduced the slope factor of the activation curve, consistent with altered voltage sensitivity of Ih gating. Immunohistochemical analysis confirmed the presence of 5-HT1A, 5-HT2A, and 5-HT2C receptors in the AVCN. Together, these findings indicate that serotonergic excitation of AVCN stellate cells is mediated by coordinated activation of multiple 5-HT receptor subtypes and primarily involves modulation of HCN-dependent subthreshold membrane dynamics. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

Figure 1

18 pages, 10330 KB

Open AccessArticle

A Salt-Responsive PvHAK12 from Paspalum vaginatum Negatively Regulates Salt Tolerance in Transgenic Arabidopsis thaliana

by Ying Zhao, Risheng Huang, Huapeng Zhou, Yuxin Chen, Mengtong Dai, Chuanqi Zhao, Siyu Ran, Fengyuan Liu, Xiangwang Xu, Minjie Wang, Zhenfei Guo and Haifan Shi

Int. J. Mol. Sci. 2026, 27(7), 3029; https://doi.org/10.3390/ijms27073029 - 26 Mar 2026

Abstract

Soil salinization has become a major global constraint threatening ecosystem stability and agricultural production. As a prominent salt-tolerant turfgrass, Paspalum vaginatum (seashore paspalum) serves as an excellent material for exploring salt tolerance mechanisms. In this study, PvHAK12, a high-affinity K⁺ transporter [...] Read more.

Soil salinization has become a major global constraint threatening ecosystem stability and agricultural production. As a prominent salt-tolerant turfgrass, Paspalum vaginatum (seashore paspalum) serves as an excellent material for exploring salt tolerance mechanisms. In this study, PvHAK12, a high-affinity K⁺ transporter (HAK) family gene isolated from seashore paspalum, was functionally characterized. PvHAK12 encodes a 788 amino acid protein with 13 transmembrane domains, belonging to the plasma membrane-localized ion transporters. It exhibits high sequence conservation with other HAK transporters and is predominantly expressed in roots and stems, with distinct tissue- and time-specific induction under salt stress. Yeast complementation assays revealed that PvHAK12 has no obvious K⁺ transport capacity but may mediate Na⁺ transport. Overexpression of PvHAK12 in Arabidopsis thaliana significantly reduced salt tolerance at germination, seedling and rosette stages, as reflected by lower germination rate, fresh weight, survival rate, the maximum quantum yield of photosystem II (Fv/Fm) value and chlorophyll content, accompanied by higher ion leakage. Under salt stress, transgenic plants accumulated more Na⁺ and less K⁺, leading to an elevated Na⁺/K⁺ ratio. Moreover, transgenic lines displayed weaker antioxidant enzyme activities and higher reactive oxygen species (ROS) accumulation. Transcript analysis further demonstrated that PvHAK12 overexpression suppressed the induction of multiple ion-transport and stress-responsive genes under salt conditions. These results indicate that PvHAK12 negatively regulates plant salt tolerance by disrupting ion homeostasis, antioxidant capacity and stress-related gene expression. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

18 pages, 9397 KB

Open AccessArticle

Antinociceptive Effect and Hyperalgesia of Fentanyl and Its Analogues

by Yuanyuan Chen, Kaixi Li, Xiangyu Li, Simeng Zhang, Deli Xu, Yawen Xu, Yanling Qiao, Yizhao Xu, Mengchan Xia, Weitao Qin, Bin Di and Peng Xu

Int. J. Mol. Sci. 2026, 27(7), 3028; https://doi.org/10.3390/ijms27073028 - 26 Mar 2026

Abstract

Fentanyl is a potent analgesic widely used in clinical practice. Fentanyl and its analogues are seriously abused and are emerging in the illegal drug market, leading to numerous intoxication cases. However, assessment of the potency of the pharmacological effect of these novel fentanyl [...] Read more.

Fentanyl is a potent analgesic widely used in clinical practice. Fentanyl and its analogues are seriously abused and are emerging in the illegal drug market, leading to numerous intoxication cases. However, assessment of the potency of the pharmacological effect of these novel fentanyl analogues remains limited and inconsistent across studies. The development of novel analgesics has largely relied on the assessment of mu opioid receptor (MOR) binding affinity, with insufficient verification through the assessment of antinociceptive effects. This study evaluated the antinociceptive effects of 25 fentanyl analogues to investigate the relationship between chemical structure and antinociceptive effect. In this study, hot plate tests were conducted in mice to generate time–effect and dose–effect curves for the evaluation of the antinociceptive effect of fentanyl and its analogues. The results demonstrated that the antinociceptive effects of fentanyl analogues were dose- and time-dependent. The potency of the antinociceptive effect observed in this study generally aligned with the corresponding MOR binding affinities reported in the literature, although several analogues exhibited discrepancies. Structural modifications in different regions of the fentanyl scaffold affect the antinociceptive potency to different degrees, and the duration of action also varied across fentanyl analogues. Furthermore, opioid-induced hyperalgesia (OIH) was observed following administration of several fentanyl analogues, raising potential concerns regarding their abuse liability and development for analgesic purposes. Taken together, this study systematically evaluated and compared the antinociceptive effects of fentanyl analogues. The findings clarify the relationship between chemical structure and the antinociceptive effect, providing valuable insights for drug regulation and the development of novel analgesics. Full article

(This article belongs to the Special Issue Mechanistic Insights into Pharmacological and Non-Pharmacological Pain Therapies: From Cellular Responses to Therapy Outcomes)

► Show Figures

Figure 1

17 pages, 2687 KB

Open AccessArticle

Dihydroartemisinin Induces Ferroptosis in Uveal Melanoma Cells Through the HO-1 and xCT/GPX4 Signaling Pathways

by Yuxuan Zhao, Chen Hou, Lirong Xiao, Longqian Liu and Naihong Yan

Int. J. Mol. Sci. 2026, 27(7), 3027; https://doi.org/10.3390/ijms27073027 - 26 Mar 2026

Abstract

Uveal melanoma (UM) represents an uncommon intraocular malignancy with high aggressiveness. Dysregulation of ferroptosis has been associated with UM progression. Dihydroartemisinin (DHA), a natural derivative of Artemisia annua, exhibits potent antitumor activity with a favorable safety profile, yet its role in ferroptosis [...] Read more.

Uveal melanoma (UM) represents an uncommon intraocular malignancy with high aggressiveness. Dysregulation of ferroptosis has been associated with UM progression. Dihydroartemisinin (DHA), a natural derivative of Artemisia annua, exhibits potent antitumor activity with a favorable safety profile, yet its role in ferroptosis regulation in UM remains unclear. Here, we showed that DHA significantly reduced the proliferation and invasiveness of UM cells—both primary and secondary—with effects intensifying over time and dose. Transcriptomic analysis indicated that DHA may exert antitumor effects by modulating the ferroptosis-related pathway, characterized by upregulating heme oxygenase-1 (HO-1) and downregulating the SLC7A11 (xCT)/GPX4 axis, leading to iron accumulation, increased ROS and lipid peroxidation, and mitochondrial dysfunction. Iron chelators and pancaspase inhibitors partially reverse these effects, whereas HO-1 inducers enhance them. Overall, our results suggest that DHA suppresses UM progression by inducing ferroptosis and mitochondrial dysfunction, while the HO-1 and xCT/GPX4 pathways may contribute to these effects. DHA may represent a potential therapeutic approach for UM, warranting further investigation. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

Figure 1

26 pages, 1411 KB

Open AccessArticle

Role of the Glycine Transporter GlyT2 in the Neuronal Differentiation of PC12 Cells

by Jorge Sarmiento-Jiménez, Beatriz Morales-González, Enrique Núñez, Elena Martínez-Blanco, Francisco Zafra, Francisco Javier Díez-Guerra and Beatriz López-Corcuera

Int. J. Mol. Sci. 2026, 27(7), 3026; https://doi.org/10.3390/ijms27073026 - 26 Mar 2026

Abstract

Hyperekplexia is a neurologic disorder of marked perinatal significance. Affected neonates display generalized hypertonia and exaggerated startle reflex in response to innocuous stimuli, potentially leading to life-threatening apneic episodes. Although symptom severity typically diminishes during the first year of life, affected individuals often [...] Read more.

Hyperekplexia is a neurologic disorder of marked perinatal significance. Affected neonates display generalized hypertonia and exaggerated startle reflex in response to innocuous stimuli, potentially leading to life-threatening apneic episodes. Although symptom severity typically diminishes during the first year of life, affected individuals often continue to exhibit disabling motor dysfunction and frequent unprotected falls throughout adulthood. Currently, no targeted therapeutic interventions are available. The pathophysiology involves partial or complete disruption of inhibitory glycinergic neurotransmission. Mutations in the gene encoding the neuronal glycine transporter GlyT2 (SLC6A5) represent the second-most frequent genetic etiology of human hyperekplexia. To investigate the mechanistic basis for the heightened severity of symptoms during the perinatal period, we examined the role of GlyT2 in neuronal differentiation using the PC12 cell model. Pharmacological induction of differentiation demonstrated that clones stably expressing GFP-GlyT2 exhibit increased expression of neuronal differentiation markers and enhanced neurite outgrowth—both in number and length—relative to parental PC12 cells. These clones also displayed elevated cytosolic calcium levels, which were attenuated by calmodulin overexpression, subsequently downregulating differentiation marker expression. We hereby proved that GlyT2 is clearly implicated in growth cone progression and differentiation of PC12 cells into neurons by increasing internal calcium and binding to growth cone proteins. Finally, our results were validated in primary neurons. Full article

(This article belongs to the Special Issue Advances in the Physiopathology of Neurodevelopmental Disorders)

► Show Figures

Graphical abstract

25 pages, 1163 KB

Open AccessArticle

Bioactivities of Alchemilla alpina L. Extract on Women’s Reproductive and Metabolic Health: Antioxidant, Enzyme Inhibitory, Receptor Modulatory Properties and Potential Cytotoxic Effects

by Sanja Krstić, Sofija Bekić, Nemanja Živanović, Andrea Pirković, Jovana Vuković, Rudolf Bauer and Milena Rašeta

Int. J. Mol. Sci. 2026, 27(7), 3025; https://doi.org/10.3390/ijms27073025 - 26 Mar 2026

Abstract

Alchemilla alpina L. (Rosaceae), belongs to a genus well recognized in traditional medicine for treating gynecological disorders and hormonal imbalance; however, the specific bioactivity of A. alpina itself remains poorly characterized. This study aimed to elucidate the phenolic composition and the biological potential [...] Read more.

Alchemilla alpina L. (Rosaceae), belongs to a genus well recognized in traditional medicine for treating gynecological disorders and hormonal imbalance; however, the specific bioactivity of A. alpina itself remains poorly characterized. This study aimed to elucidate the phenolic composition and the biological potential of the methanolic (MeOH) extract of A. alpina. LC–MS/MS analysis identified 39 phenolic compounds, with rutin, catechin, kaempferol-3-O-glucoside, and caffeic acid being the dominant constituents. The extract exhibited high total phenolic and flavonoid contents, consistent with strong antioxidant capacities. It demonstrated notable α-glucosidase and acetylcholinesterase inhibitory activities, indicating its potential relevance for metabolic and neurodegenerative disorders. The extract effectively reduced AAPH-induced ROS levels in MRC-5 fibroblasts, indicating cytoprotective and antioxidative effects. The cytotoxicity toward cervical cancer cells HeLa and ovarian cancer cells A2780 was moderate and concentration dependent. A yeast-based fluorescent screen revealed a strong and selective binding affinity toward estrogen receptor α (ERα) and selective inhibition of human recombinant AKR1C3 (59.5%), without affecting AKR1C4. Additionally, high COX-1/COX-2 inhibition (>70%) supported its anti-inflammatory potential. Collectively, these findings provide the first integrated evidence of A. alpina’s phenolic richness and multifunctional bioactivity, scientifically supporting its potential in managing hormone-dependent and oxidative stress-related disorders. Full article

(This article belongs to the Special Issue Role of Natural Products in Health and Diseases)

► Show Figures

Figure 1

23 pages, 5464 KB

Open AccessArticle

Placental Histiocyte Phenotypes in Chronic Histiocytic Intervillositis: A Comprehensive Immunophenotypic and Morphologic Atlas

by Elise Gradhand, Luisa Strahler, Julia Bein, Margarete Mijatovic, Hannah-Ida Hullmeine, Andreas Weigert, Stephan Spahn, Eva Herrmann, Franz Bahlmann and Ella Hullmeine

Int. J. Mol. Sci. 2026, 27(7), 3024; https://doi.org/10.3390/ijms27073024 - 26 Mar 2026

Abstract

Chronic histiocytic intervillositis (CHI) is a placental lesion characterized by an inflammatory response, significantly influencing maternal and fetal outcomes. This study aims to develop a comprehensive morphologic atlas detailing the localization of fetal and maternal macrophages within the context of CHI. We employed [...] Read more.

Chronic histiocytic intervillositis (CHI) is a placental lesion characterized by an inflammatory response, significantly influencing maternal and fetal outcomes. This study aims to develop a comprehensive morphologic atlas detailing the localization of fetal and maternal macrophages within the context of CHI. We employed immunohistochemical and multiplexing techniques to analyze placental samples, identifying expression patterns and spatial distribution of key macrophage markers, including CD68, CD163, CD14, and HLA-DR. The results revealed a marked accumulation of activated macrophages in both the intervillous space and villous stroma, with distinct differences in morphology and immunophenotype of fetal Hofbauer cells versus maternal macrophages. Our findings contribute to a better understanding of the immune landscape in CHI and provide a valuable resource for further research into placental immune dynamics. By establishing this morphologic atlas, we aim to enhance diagnostic and therapeutic strategies for affected pregnancies, thereby improving the diagnostic approach and making it more straightforward to recognize CHI histologically. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

3 pages, 135 KB

Open AccessEditorial

Special Issue “Properties and Applications of Nanoparticles and Nanomaterials: 3rd Edition”

by Xiaogang Li

Int. J. Mol. Sci. 2026, 27(7), 3023; https://doi.org/10.3390/ijms27073023 - 26 Mar 2026

Abstract

In recent years, we have witnessed the rapid evolution of nanomaterials, accompanied by a significant surge in scholarly and industrial interest [...] Full article

(This article belongs to the Special Issue Properties and Applications of Nanoparticles and Nanomaterials: 3rd Edition)

2 pages, 154 KB

Open AccessReply

Reply to Kriventsov, M.A.; Neprelyuk, O.A. Resolvins Revisited: Methodological and Translational Gaps. Comment on “Ghemiș et al. The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review. Int. J. Mol. Sci. 2024, 25, 12784”

by Larisa Ghemiș, Ancuta Goriuc and Ionut Luchian

Int. J. Mol. Sci. 2026, 27(7), 3022; https://doi.org/10.3390/ijms27073022 - 26 Mar 2026

Abstract

We would like to express our sincere gratitude to the authors of the comment for their careful reading and insightful observations regarding our recently published review, “The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative [...] Read more.

We would like to express our sincere gratitude to the authors of the comment for their careful reading and insightful observations regarding our recently published review, “The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review” [...] Full article

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

17 pages, 2485 KB

Open AccessArticle

Renoprotective Potential of Nateglinide in an Acute Kidney Injury Model

by Senanur Ilıkça, Samet Öz, Güldeniz Şekerci, Aslı Taşlıdere and Suat Tekin

Int. J. Mol. Sci. 2026, 27(7), 3021; https://doi.org/10.3390/ijms27073021 - 26 Mar 2026

Abstract

Nateglinide (Nat) is an oral antidiabetic agent of the meglitinide class that has been reported to exert protective effects beyond glycemic control, particularly against oxidative stress and inflammation. Since oxidative stress and inflammation play a key role in the pathogenesis of acute kidney [...] Read more.

Nateglinide (Nat) is an oral antidiabetic agent of the meglitinide class that has been reported to exert protective effects beyond glycemic control, particularly against oxidative stress and inflammation. Since oxidative stress and inflammation play a key role in the pathogenesis of acute kidney injury (AKI), especially following ischemia/reperfusion (I/R), this study aimed to evaluate the potential renoprotective effects of Nat in a rat model of I/R-induced AKI. Forty male Sprague Dawley rats were randomly divided into four groups (n = 10): Control, I/R, I/R + Nat (50 mg/kg), and I/R + Nat (100 mg/kg). Bilateral renal ischemia was induced by clamping renal arteries for 45 min, followed by 24 h of reperfusion. Nat was administered orally 1 h before ischemia. Renal levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and thiobarbituric acid reactive substances (TBARSs) were assessed. Serum blood urea nitrogen (BUN), creatinine, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were also measured, and histopathological analyses were performed. Nat significantly increased renal antioxidant parameters and reduced TBARS levels. Moreover, Nat markedly decreased serum BUN, creatinine, TNF-α, and IL-1β levels compared with the I/R group (p < 0.05). Histopathology confirmed attenuated renal damage in Nat-treated groups (p < 0.0001). These results indicate that Nat confers significant renoprotection against renal I/R injury via suppression of oxidative stress and inflammation. Full article

(This article belongs to the Topic Animal Models of Human Disease 3.0)

► Show Figures

Figure 1

18 pages, 4264 KB

Open AccessArticle

Expansion and Functional Divergence of Shaker K⁺ Channels in Bermudagrass Highlight CdKAT1.1 in Salt Tolerance

by Dong-Li Hao, Jia Qu, Jun-Yi Zhai, Rui-Qi Zhang, Shu-Yan Xi, Xi Xiang, Rong-Rong Chen, Hai-Lin Guo, Jun-Qin Zong and Jing-Bo Chen

Int. J. Mol. Sci. 2026, 27(7), 3020; https://doi.org/10.3390/ijms27073020 - 26 Mar 2026

Abstract

Salt stress inhibits plant growth, requiring salt-tolerant genes for the development of resilient plants. A key tolerance mechanism is potassium/sodium homeostasis, governed by Shaker K⁺ channels. Given that Shaker K⁺ channels from salt-sensitive species have been extensively studied while their counterparts [...] Read more.

Salt stress inhibits plant growth, requiring salt-tolerant genes for the development of resilient plants. A key tolerance mechanism is potassium/sodium homeostasis, governed by Shaker K⁺ channels. Given that Shaker K⁺ channels from salt-sensitive species have been extensively studied while their counterparts in salt-tolerant plants remain largely unexplored, this study investigates the evolution and function of these channels in salt-tolerant bermudagrass to address this knowledge gap. Genomic analysis identified 25 Shaker K⁺ channel genes, an expanded family relative to other species. Phylogenetics placed them into five groups (I–V), with groups I, II, III, and V expanded via segmental duplication. Salt stress response screening revealed that only CdKAT1.1 was rapidly upregulated. Functional assays in yeast demonstrated that both CdKAT1.1 and its closest homolog CdKAT1.2 improve potassium uptake and salt tolerance, but the enhancement from CdKAT1.1 was significantly greater. This work elucidates the expansion and functional divergence of Shaker K⁺ channels in bermudagrass. CdKAT1.1 emerges as a superior regulator of potassium efficiency and salt tolerance, making it a prime candidate for molecular breeding to improve plant resilience in saline-alkaline soils. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Plant Adaptation to Stress)

► 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