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Int. J. Mol. Sci., Volume 27, Issue 10 (May-2 2026) – 497 articles

Cover Story (view full-size image): The development of innovative theranostic systems represents a crucial opportunity in nuclear medicine. In this study, we propose a multiscale approach for a theranostic platform based on AuNRs functionalized with radiopharmaceuticals. AuNRs offer a versatile system due to their unique physicochemical properties and surface functionalization capabilities. Key challenges include targeting the cell nucleus, loading AuNRs with radiopharmaceuticals, and investigating Auger electron emission under gamma irradiation. Multiscale modelling describes the system behaviour and predicts radiobiological enhancement, including synergistic interactions with 99mTc-sestaMIBI. Experimental activity includes gamma irradiation studies, structural characterization, and in vitro investigations on T98G cells to evaluate cytotoxicity and metabolic alterations. View this paper
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24 pages, 1525 KB  
Review
Molecular Mechanisms Underlying Alzheimer’s Disease Pathogenesis: Comprehensive Overview
by Filomena Lo Vecchio, Annamaria la Torre, Carolina Gravina, Grazia D’Onofrio and Antonio Greco
Int. J. Mol. Sci. 2026, 27(10), 4651; https://doi.org/10.3390/ijms27104651 - 21 May 2026
Cited by 2 | Viewed by 15740
Abstract
Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological [...] Read more.
Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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24 pages, 936 KB  
Article
An Efficient Method for Contraction of Property-Oriented Basis Sets: A Considerable Reduction of the pecJ-1 and pecJ-2 Basis Sets for the Calculations of Spin–Spin Coupling Constants Involving H, C, N and F Nuclei
by Irina L. Rusakova and Yuriy Yu. Rusakov
Int. J. Mol. Sci. 2026, 27(10), 4650; https://doi.org/10.3390/ijms27104650 - 21 May 2026
Viewed by 529
Abstract
In this paper, it is suggested that the property–energy consistent (PEC) method represents an efficient and reliable method for generating accurate contraction coefficients for the property-oriented basis sets. Due to its peculiarities, the PEC method allows the implementation of rather succinct contraction schemes, [...] Read more.
In this paper, it is suggested that the property–energy consistent (PEC) method represents an efficient and reliable method for generating accurate contraction coefficients for the property-oriented basis sets. Due to its peculiarities, the PEC method allows the implementation of rather succinct contraction schemes, without a noticeable loss of accuracy, giving in result very compact property-oriented basis sets that are capable of providing the same or even better accuracy than that reached with considerably larger basis sets of the same kind. This idea has been demonstrated on the example of the recontraction of previously introduced spin–spin coupling constant (SSCC)-oriented pecJ-n (n = 1, 2) basis sets for H, C, N, and F atoms, whose exponents were optimized by the PEC algorithm, but the contraction coefficients were defined using the usual self-consistent field calculations of the molecular energies of the simplest hydrides. In this work, the original pecJ-n basis sets were recontacted by means of the PEC method, resulting in compact segmented–contracted basis sets being smaller in size than their previous analogies by four and seven functions for hydrogen and the 2nd-period atoms, respectively. High-quality SOPPA(CCSD) calculations of 436 SSCCs of various types involving H, C, N, and F nuclei showed the supremacy of the newly contracted pecJ-n (n = 1, 2) basis sets over their original versions and most of the other well-known SSCC-oriented basis sets. Full article
(This article belongs to the Topic Theoretical, Quantum and Computational Chemistry—2nd Edition)
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24 pages, 794 KB  
Review
Clinical Applications of Blood-Derived Extracellular Vesicle Biomarkers in Breast Cancer: A Scoping Review
by Eun-Gyeong Lee, Kyung-Hee Kim, Se Bin Kim, Young Chan Chae, Min-Chae Kang and Sun-Young Kong
Int. J. Mol. Sci. 2026, 27(10), 4649; https://doi.org/10.3390/ijms27104649 - 21 May 2026
Viewed by 746
Abstract
Blood-derived extracellular vesicle (EV) biomarkers have emerged as promising liquid-biopsy analytes for monitoring treatment response and prognosis in breast cancer. This scoping review mapped the clinical evidence on blood-derived EV in breast cancer and identified key barriers to clinical translation. Following the Joanna [...] Read more.
Blood-derived extracellular vesicle (EV) biomarkers have emerged as promising liquid-biopsy analytes for monitoring treatment response and prognosis in breast cancer. This scoping review mapped the clinical evidence on blood-derived EV in breast cancer and identified key barriers to clinical translation. Following the Joanna Briggs Institute framework and PRISMA-ScR guidelines, we searched PubMed, Embase, and Web of Science for eligible studies published through November 2025. After duplicate removal, title and abstract screening, and full-text assessment, 64 clinical studies were included. Research activity increased markedly from 2020 onward, accounting for 87.5% (56/64) of included studies. The literature was concentrated in East Asia, particularly China (51.6%, 33/64). RNA-based biomarkers predominated (60.9%, 39/64), especially microRNAs (39.1%, 25/64). Prognostic outcomes were evaluated in 89.1% (57/64) of studies, treatment response in 51.6% (33/64), and both endpoints in 40.6% (26/64). Triple-negative breast cancer was the most frequently studied subtype in isolation (15.6%, 10/64). Methodological heterogeneity was substantial, and kit-based precipitation was the most common EV isolation method (57.8%, 37/64). EV biomarkers show promise for non-invasive monitoring in breast cancer, but methodological standardization, compliance with Minimal Information for Studies of Extracellular Vesicles guidelines, and large prospective validation studies remain necessary before routine clinical implementation. Full article
(This article belongs to the Section Molecular Oncology)
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43 pages, 1311 KB  
Review
Risk Factors for Hepatocellular Carcinoma in Latino Populations in Texas: A Scoping Review
by Lais Yuki Tuzino Kamia, Emily Gonzalez, Cassandra M. Swanson, Stephanie L. Gomez, Ariann M. Canales and Ramona Salcedo Price
Int. J. Mol. Sci. 2026, 27(10), 4648; https://doi.org/10.3390/ijms27104648 - 21 May 2026
Viewed by 883
Abstract
Hepatocellular carcinoma (HCC) incidence in Texas is 45% higher than the national average, with disproportionate burden among the Hispanic/Latino population. Despite significant health disparities, comprehensive evidence on HCC risk factors specific to this population remains limited. This scoping review of 20 primarily observational [...] Read more.
Hepatocellular carcinoma (HCC) incidence in Texas is 45% higher than the national average, with disproportionate burden among the Hispanic/Latino population. Despite significant health disparities, comprehensive evidence on HCC risk factors specific to this population remains limited. This scoping review of 20 primarily observational studies utilized PubMed, EbscoHost, and the PRISMA-ScR checklist to map risk factors in south Texas. Results show that metabolic dysfunction, specifically diabetes and obesity, increases advanced liver disease odds by 7- to 12-fold compared to non-Hispanic groups. Environmental exposures are also significant: aflatoxin was detected in 5.7 to 7.3% of Hispanic/Latino HCC tumors, and cases demonstrated 6-fold higher odds of aflatoxin biomarkers, while alcohol contributed to 3.0% of cancers. Furthermore, PNPLA3 genetic variants exerted synergistic effects with obesity and heavy alcohol consumption. Among four intervention studies, strategies included low-dose calcium montmorillonite clay for aflatoxin reduction, community-health-worker-integrated chronic care, and hospital-based hepatitis screening. However, critical research gaps remain regarding multirisk factor interactions, toxin dose–response characterization, dietary interventions, and longitudinal data. These findings underscore the urgent need for culturally tailored, community-engaged prevention programs and ethnicity-specific HCC guidelines for the Texas Hispanic/Latino population to effectively address these rising health disparities. Full article
(This article belongs to the Special Issue Liver Disease and Primary Liver Cancer: Translational Advances and Therapeutic Perspectives)
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17 pages, 9793 KB  
Article
The Upregulation of AIM2 in the Central Nucleus of the Amygdala Correlates with Pain Induced by Tooth Movement
by Rui Wang, Yutong Guo, Weining Wang, Yuhuan Jiang, Tingting Lin, Wenhui Liang, Bing Qi and Hu Qiao
Int. J. Mol. Sci. 2026, 27(10), 4647; https://doi.org/10.3390/ijms27104647 - 21 May 2026
Cited by 1 | Viewed by 483
Abstract
Pain is an unavoidable experience during orthodontic treatment. The central nucleus of the amygdala (CeA) plays a key role in regulating emotion and pain. Meanwhile, Absent in Melanoma 2 (AIM2) has been demonstrated in multiple neuroinflammatory and pain models for promoting inflammatory responses [...] Read more.
Pain is an unavoidable experience during orthodontic treatment. The central nucleus of the amygdala (CeA) plays a key role in regulating emotion and pain. Meanwhile, Absent in Melanoma 2 (AIM2) has been demonstrated in multiple neuroinflammatory and pain models for promoting inflammatory responses then enhancing nociceptive signaling. However, its role in pain caused by orthodontic tooth movement has not yet been clarified. In this study, C57BL/6J mice were used to establish an experimental tooth movement (ETM) model and were assigned to a control group, sham group, and experimental group. The face grooming and von Frey results showed that pain behaviors reached a peak on 1 d and returned to baseline levels by 7 d. After 14 days of continuous force application, mice developed obvious anxious behaviors and progressively worsened over time. The Western blot results revealed that tooth movement significantly increased AIM2 protein expression in the CeA. This was accompanied by a marked upregulation of NLRP3, caspase-1 and pp65. These findings suggest a potential role of NLRP3-NF-κB signaling in orthodontic tooth movement and also provide a new central target for the precise regulation of orthodontic pain. Full article
(This article belongs to the Special Issue Oral Soft Tissue Repair and Oral Diseases: 2nd Edition)
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15 pages, 2010 KB  
Article
N- and O-glycans in Unfertilized Chum Salmon (Oncorhynchus keta) Eggs Using Glycomic Techniques
by Masaki Kurogochi, Kai Suzuki, Di Wu, Hisatoshi Hanamatsu, Ken Kitajima, Chihiro Sato and Jun-ichi Furukawa
Int. J. Mol. Sci. 2026, 27(10), 4646; https://doi.org/10.3390/ijms27104646 - 21 May 2026
Viewed by 571
Abstract
Genomic analysis of various fish has advanced in recent years; however, predicting glycan information from the genomic data alone remains challenging. Glycomic techniques have therefore attracted considerable attention. In this study, we analyzed N- and O-glycans in unfertilized Oncorhynchus keta eggs [...] Read more.
Genomic analysis of various fish has advanced in recent years; however, predicting glycan information from the genomic data alone remains challenging. Glycomic techniques have therefore attracted considerable attention. In this study, we analyzed N- and O-glycans in unfertilized Oncorhynchus keta eggs using glycomic techniques, such as a glycoblotting procedure, a sialic acid linkage-specific alkylamidation, and an evaporative β-elimination with pyrazolone. N-Glycomic analysis revealed that biantennary N-glycans were predominant, and that sialylation occurred via an α2,3 linkage. In addition, numerous sulfated N-glycans were observed, some of which had not been reported previously. Tandem mass spectrometry analyses indicated that most of the sulfate groups were attached to GlcNAc linked to mannose within the core structure. The sulfation sites of the unknown sulfated glycans were the same; however, a GlcNAc residue was lost from the core structure. In O-glycomics, oligo-sialylated O-glycans, which contain between one to seven sialic acid residues, were observed in the unfertilized eggs. Most of the sialic acids in the O-glycans were Neu5Gc, and there was no α2,3 linkage. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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12 pages, 2799 KB  
Article
Exploratory Expression Analysis of Stem Cell and Epithelial–Mesenchymal Transition Markers in Ameloblastoma
by Luis Alberto Martínez-Marcial, Josué Orlando Ramírez-Jarquín, Francisco German Villanueva-Sánchez, Javier Portilla-Robertson, Carla Monserrat Ramírez-Martínez, David Alonso Trejo-Remigio, Claudia Patricia Mejía-Velázquez, Luis Pablo Cruz-Hervert and Luis Fernando Jacinto-Alemán
Int. J. Mol. Sci. 2026, 27(10), 4645; https://doi.org/10.3390/ijms27104645 - 21 May 2026
Viewed by 622
Abstract
Ameloblastoma is a common benign odontogenic tumor. Its etiology has been associated with dysregulation of the MAPK and SHH pathways, and new theories suggest that tumor stem cells (TSCs) and the epithelial–mesenchymal transition (EMT) are participants in their pathogenesis. Objective: To determine the [...] Read more.
Ameloblastoma is a common benign odontogenic tumor. Its etiology has been associated with dysregulation of the MAPK and SHH pathways, and new theories suggest that tumor stem cells (TSCs) and the epithelial–mesenchymal transition (EMT) are participants in their pathogenesis. Objective: To determine the immunohistochemical expression of SOX2 and CD44 as indicators of TSCs and the gene expression of vimentin, smooth muscle actin, and FGFR1 as indicators of the EMT in conventional, unicystic, and peripheral ameloblastoma. Materials and Methods: Conventional, unicystic, and peripheral ameloblastomas and dental follicles, as a control group, were analyzed by peroxidase immunohistochemistry assays for SOX2 and CD44 as TSC-related markers, and the EMT relationship was determined by RT-qPCR expression for vimentin (VIM), alpha smooth muscle actin (ACTA2), fibroblast growth factor receptor 1 (FGFR1), and GAPDH as a control. Results: The most affected anatomical site was the mandible, with an average age of 38.03 (±20.95) years. SOX2 and CD44 immunoexpression were significantly higher in conventional ameloblastoma. RT-qPCR results showed predominant non-significant expression of VIM, ACTA2, and FGFR1 in unicystic ameloblastoma compared to other ameloblastoma types. Conclusion: The significantly higher immunoexpression of SOX2 and CD44 in conventional subtypes could suggest a greater presence of TSCs, and predominant VIM, ACTA2, and FGFR1 gene expression in unicystic ameloblastoma could suggest the possibility of EMT processes related to cystic formation. More research on TSCs and the EMT is necessary to elucidate this finding. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Oral Pathology)
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11 pages, 1252 KB  
Article
miRNA-26b Is Associated with Increased Connexin-40 Expression in Endothelial Cells Under Flow Conditions
by Marcus Igl, Markus Haberbosch, Michael Hristov, Felix Reich, Emiel P. C. van der Vorst, Christian Weber and Kiril Bidzhekov
Int. J. Mol. Sci. 2026, 27(10), 4644; https://doi.org/10.3390/ijms27104644 - 21 May 2026
Viewed by 733
Abstract
Endothelial cell dysfunction is the initial step in atherosclerosis, in which gap junction proteins such as connexin 40 (Cx40) might play an important role. Previously, we could demonstrate that miRNA-26b, a 21-nucleotide miRNA, is highly expressed in human atherosclerotic plaques and plays a [...] Read more.
Endothelial cell dysfunction is the initial step in atherosclerosis, in which gap junction proteins such as connexin 40 (Cx40) might play an important role. Previously, we could demonstrate that miRNA-26b, a 21-nucleotide miRNA, is highly expressed in human atherosclerotic plaques and plays a key causal role in atherogenesis. There is evidence that miRNA-26b and Cx40 play crucial roles in sustaining endothelial health. However, their potential effects on atherosclerosis-related processes remain poorly understood. Therefore, this study elucidated the expression of miRNA-26b and Cx40 and studied the effect of Cx40 on inflammation and monocyte binding, which are key processes in atherosclerosis formation. In a human in vitro endothelial cell model, miRNA-26b overexpression is associated with increased Cx40 expression. Although we did not observe any anti-atherogenic effect of Cx40 on monocyte attachment or VCAM-1 transcription under static conditions, a flow-dependent expression pattern characterised by increased Cx40 and reduced VCAM-1 transcription was observed. How miRNA-26b and Cx40 are connected remains to be investigated. Furthermore, the functional role of Cx40 under flow conditions requires further investigation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction, Fifth Edition)
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12 pages, 961 KB  
Article
Mutation Spectrum of ADAMTS13 Gene in Patients with Upshaw–Schulman Syndrome (USS) in Russia
by Julia Poznyakova, Olesya Pshenichnikova, Elizaveta Klebanova, Gennadiy Galstyan and Vadim Surin
Int. J. Mol. Sci. 2026, 27(10), 4643; https://doi.org/10.3390/ijms27104643 - 21 May 2026
Viewed by 1034
Abstract
Upshaw–Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the [...] Read more.
Upshaw–Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the formation of platelet thrombi in the microcirculation, accompanied by hemolytic anemia, thrombocytopenia, and clinical and laboratory signs of renal and neurological failure. The aim of this study was to describe the ADAMTS13 gene mutation spectrum in the Russian population. We analyzed the ADAMTS13 gene in 45 unrelated patients with TTP of unknown origin. DNA was extracted from blood cells using the phenol-chlorophorm method, and all exons of the gene were investigated using Sanger sequencing. In 15 out of 45 patients, we identified 20 different variants associated with USS, including two frameshift, two variants affecting the splice site, one nonsense and fifteen missense mutations. Eight out of those mutations were previously undescribed. Tree variants were revealed more than once: p.Arg1060Trp (7 patients), p.Glu1326ArgfsTer6 (7 patients) and p.Cys1067SerfsTer30 (3 patients). Variants (p.Arg1060Trp) and p.Glu1326ArgfsTer6 prevailed in the global population; however, p.Cys1067SerfsTer30 was not previously described in the European population. Our results expand the existing knowledge of the molecular basis of USS and may contribute to improved genetic diagnostics in Russia. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances: 2nd Edition)
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61 pages, 14548 KB  
Review
A Review of Approaches to the Synthesis of DCL-Based Prostate-Specific Membrane Antigen Ligands
by Nikolai Y. Zyk, Nina S. Butakova, Aleksei E. Machulkin and Elena K. Beloglazkina
Int. J. Mol. Sci. 2026, 27(10), 4642; https://doi.org/10.3390/ijms27104642 - 21 May 2026
Cited by 1 | Viewed by 950
Abstract
Prostate-specific membrane antigen (PSMA) ligands are currently one of the popular platforms for creating drugs targeted at prostate cancer tumor cells. In this review, we have collected and systematized current approaches to the synthesis of PSMA ligands based on N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S [...] Read more.
Prostate-specific membrane antigen (PSMA) ligands are currently one of the popular platforms for creating drugs targeted at prostate cancer tumor cells. In this review, we have collected and systematized current approaches to the synthesis of PSMA ligands based on N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL), the most widely used scaffold in the design of such ligands. The main approaches to each stage of the synthesis of PSMA inhibitors with various structures are considered in detail, and the existing synthetic techniques are compiled and analyzed. We also review examples of using different synthetic pathways for diagnostic and therapeutic drugs based on PSMA ligands. We propose an algorithm for selecting a synthetic route based on the structure of the target ligand. Full article
(This article belongs to the Special Issue Prostate Cancer Research Update: Molecular Diagnostic Biomarkers)
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20 pages, 14999 KB  
Article
Investigating the Effects and Potential Mechanisms of Astragalus Root Against Diabetic Nephropathy Based on Bioinformatics Analysis and In Vitro Validation
by Jie Li, Subinur Ahmattohti, Ying Gao, Xiangqin Xie, Jasur Kasim, Liang Feng, Baojian Li, Shuliang Niu and Jianguang Li
Int. J. Mol. Sci. 2026, 27(10), 4641; https://doi.org/10.3390/ijms27104641 - 21 May 2026
Viewed by 1180
Abstract
Astragalus root, a traditional Chinese herbal remedy, has shown potential benefits against diabetic nephropathy (DN). However, the mechanisms driving its effects remain poorly understood. This study explored the molecular pathways through which Astragalus root improves DN. To identify possible targets and mechanisms of [...] Read more.
Astragalus root, a traditional Chinese herbal remedy, has shown potential benefits against diabetic nephropathy (DN). However, the mechanisms driving its effects remain poorly understood. This study explored the molecular pathways through which Astragalus root improves DN. To identify possible targets and mechanisms of Astragalus root in DN treatment, we applied network pharmacology, molecular docking, molecular dynamics simulation, and in vitro assays. Network pharmacology screening uncovered 46 overlapping targets between Astragalus root and DN. Protein–protein interaction (PPI) network analysis identified five core candidate targets: CASP3, VEGFA, CTNNB1, MYC, and PRKCB (PKCβ). KEGG pathway analysis indicated that the AGE-RAGE signaling pathway was the most significantly enriched. Molecular docking revealed that quercetin, β-carotene, daidzein, capsaicin, and kaempferol—potential bioactive components of Astragalus root—bound strongly to each of the five core targets. Molecular dynamics simulations further confirmed the conformational stability of kaempferol when complexed with these target proteins. In vitro experiments showed that kaempferol markedly reduced protein levels of α-SMA, Col I, and Col IV; lowered secretion of TNF-α, IL-6, and IL-1β; and decreased ROS and MDA content. Additionally, kaempferol’s therapeutic effects were mediated through suppression of the AGE-RAGE-PKCβ-TGF-β1 signaling axis. This work identified kaempferol, a bioactive ingredient of Astragalus root, as a potential therapeutic agent against DN, along with its target pathways. These findings provide a scientific foundation for its clinical translation. Full article
(This article belongs to the Special Issue Drug Discovery and Development for Renal Disease Treatment)
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19 pages, 4821 KB  
Article
Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus
by Alma N. Díaz-Herreros, Elba Reyes-Maldonado, Erika Rosales-Cruz, Fernando Gómez-Chávez, Amaranta Sarai Valdez-Guerrero, Octavio Rodríguez-Cortés, Juan C. Cancino-Díaz and Mario E. Cancino-Díaz
Int. J. Mol. Sci. 2026, 27(10), 4640; https://doi.org/10.3390/ijms27104640 - 21 May 2026
Viewed by 584
Abstract
The VHL–HIF-1α–VEGF axis regulates angiogenesis and metabolism. Beyond oncology, pVHL is essential for pancreatic β-cell function and is reduced in hypercaloric diet (HCD)-induced type 2 diabetes mellitus (T2DM). This study aimed to overexpress pVHL in pancreatic tissue and evaluate its effects on blood [...] Read more.
The VHL–HIF-1α–VEGF axis regulates angiogenesis and metabolism. Beyond oncology, pVHL is essential for pancreatic β-cell function and is reduced in hypercaloric diet (HCD)-induced type 2 diabetes mellitus (T2DM). This study aimed to overexpress pVHL in pancreatic tissue and evaluate its effects on blood glucose levels and the expression of proteins related to glucose metabolism in the pancreas. HCD-induced diabetic C57BL/6 and BALB/c mice received a single intrapancreatic injection of an adenoviral vector (1 × 1012 viral particles) encoding the murine Vhlh gene (AdVHL) to induce transient pVHL overexpression. The glycemic delta (post-load glucose minus fasting) and net incremental area under the curve (niAUC) were determined on days 3, 6, 9, 12, and 15 post-treatment, as the peak in GFP overexpression (used as a surrogate reporter of transduction efficiency) was detected between days 9 and 12. Immunohistochemistry (IHC) and immunofluorescence (IF) were used to assess the expression of pVHL, HIF-1α, GLUT-1, GLUT-2, and insulin in pancreatic tissue. AdVHL treatment significantly decreased the glycemic delta and niAUC in mice with T2DM (p < 0.01). On day 15 after treatment, HIF-1α and GLUT-1 expression were markedly reduced in AdVHL-treated mice (p < 0.01), while GLUT-2 and insulin were significantly increased (p < 0.01). These results were reproduced in both mouse strains. Transient overexpression of pVHL in pancreatic tissue of mice with T2DM was associated with decreased glucose levels and changes in the expression of proteins related to glucose metabolism in the pancreas, resembling a healthier phenotype than that of mice with T2DM. These findings support an important functional role of the pVHL–HIF-1α axis in pancreatic physiology, provide a proof-of-concept for further mechanistic and translational studies, and implicate pVHL in the altered glucose metabolism observed in T2DM. Full article
(This article belongs to the Special Issue Molecular Biology of Hypoxia: 2nd Edition)
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12 pages, 7010 KB  
Brief Report
Identification of Pathogenic Variants in CYP4F22, FLG, ALOX12B, and NIPAL4 in a Case Series of Inherited Ichthyosis
by Malali Abdul Sattar, Amna Aurang Zaib, Huda Abbasi, Mirza Zain Ul Abideen, Saima Riazuddin, Zubair M. Ahmed and Muhammad Naeem
Int. J. Mol. Sci. 2026, 27(10), 4639; https://doi.org/10.3390/ijms27104639 - 21 May 2026
Viewed by 896
Abstract
Inherited ichthyoses are clinically and genetically heterogeneous disorders of cornification caused by disruption of epidermal barrier genes involved in keratinization and lipid homeostasis. Pathogenic variants in more than 50 genes have been implicated in nonsyndromic ichthyosis vulgaris (IV) and autosomal recessive congenital ichthyosis [...] Read more.
Inherited ichthyoses are clinically and genetically heterogeneous disorders of cornification caused by disruption of epidermal barrier genes involved in keratinization and lipid homeostasis. Pathogenic variants in more than 50 genes have been implicated in nonsyndromic ichthyosis vulgaris (IV) and autosomal recessive congenital ichthyosis (ARCI). Here, we investigated the genetic basis of ichthyosis in four consanguineous Pakistani families presenting with IV or ARCI phenotypes. Exome sequencing followed by segregation analysis identified pathogenic variants in four established ichthyosis-associated genes: CYP4F22, FLG, ALOX12B, and NIPAL4. Identified variants include one novel nonsense allele of CYP4F22 (c.296G>A; p.Trp99*) and three known variants previously not reported in the Pakistani population. These known variants include a nonsense change in FLG, a frameshift allele of ALOX12B, and a missense variant in NIPAL4. Standardized phenotypic annotation using Human Phenotype Ontology terms revealed overlapping but variable clinical features across families, consistent with known genotype–phenotype heterogeneity in inherited ichthyosis. In silico protein modeling using AlphaFold2 and Ramachandran plot analysis predicted structural perturbations associated with the identified variants, supporting their pathogenic relevance. Publicly available scRNAseq datasets revealed greater heterogeneity of keratinocyte-associated expression patterns of these ichthyosis-associated genes in aging samples. Collectively, our findings expand the allelic and phenotypic spectrum of inherited ichthyosis in the Pakistani population and highlight the utility of comprehensive genetic analysis in consanguineous families for accurate molecular diagnosis, genetic counseling, and disease epidemiology. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)
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19 pages, 89538 KB  
Article
Chronic Lymphocytic Leukemia (CLL)-Derived Extracellular Vesicles (EVs) Modulate Monocytes to Become CLL-Supportive Cells
by Shaked Noah, Einat Be’ery, Zinab Sarsor, Aladin Samara, Pia Raanani and Orit Uziel
Int. J. Mol. Sci. 2026, 27(10), 4638; https://doi.org/10.3390/ijms27104638 - 21 May 2026
Viewed by 677
Abstract
In light of our previous publication, we hypothesized that chronic lymphocytic leukemia (CLL) cells also recruit monocytes to acquire survival advantage. To test this, we treated Buffy coat-driven monocytes with exosomes isolated from the peripheral blood of 45 treatment-naïve patients. The CLL-derived exosomes [...] Read more.
In light of our previous publication, we hypothesized that chronic lymphocytic leukemia (CLL) cells also recruit monocytes to acquire survival advantage. To test this, we treated Buffy coat-driven monocytes with exosomes isolated from the peripheral blood of 45 treatment-naïve patients. The CLL-derived exosomes turned monocytes into IL-6-producing cells as an increase of 13-fold in the IL-6 levels was obtained in the growth medium of the exposed monocytes. Subsequently, we filtered out the monocytes and added CLL cells to this IL-6 enriched medium. As a result, the oncogene STAT3 became phosphorylated, and thus may have provided the cells with a survival advantage. A total of 67 phosphoproteins were upregulated in response to CLL-derived exosomal exposure in the recipient monocytes, with TFIIF being among the top scored proteins in this analysis. Transfection of monocytes with a TFIIF-containing vector increased the levels of IL-6 about 14-fold in the culture medium. Importantly, the CLL-derived exosomes induced the transformation of a portion of the recipient monocytes (45% compared to 30% of the unexposed cells) to become nurse-like fibrocyte cells. Taken together, CLL cells communicate with monocytes through the exosomes that they release. Once they are taken up by monocytes, they turn them into IL-6-producing cells, which provide a survival advantage to the neoplastic cells, creating a vicious circle that promotes disease progression. Full article
(This article belongs to the Special Issue Current Insights into the Role of Exosomes in Intercellular Communication, 2nd Edition)
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12 pages, 2386 KB  
Brief Report
GM-CSF Promotes Superior In Vitro Differentiation of MHC II+ CD11c+ APCs Compared to L-929 Supernatant in Mouse Bone Marrow Cultures
by Gabriel Cordeiro, Felipe Cezar Pinheiro de Mato, Amanda Pires Bonfanti, Liana Verinaud and Catarina Rapôso
Int. J. Mol. Sci. 2026, 27(10), 4637; https://doi.org/10.3390/ijms27104637 - 21 May 2026
Viewed by 520
Abstract
Antigen-presenting cells (APCs) play a critical role in modulating immune responses, making the optimization of their differentiation protocols essential for advancing cell-based immunotherapies. This study evaluated eight protocols to differentiate APCs from bone marrow precursors of C57BL/6J mice, comparing the effects of GM-CSF [...] Read more.
Antigen-presenting cells (APCs) play a critical role in modulating immune responses, making the optimization of their differentiation protocols essential for advancing cell-based immunotherapies. This study evaluated eight protocols to differentiate APCs from bone marrow precursors of C57BL/6J mice, comparing the effects of GM-CSF and L-929 conditioned supernatants at various concentrations. Four groups treated with GM-CSF and four with L-929 supernatant, alongside a control group, were assessed. Flow cytometry analysis revealed that GM-CSF significantly increased the yield of CD11c+ MHC II+ cells by up to 6-fold compared to the L-929 supernatant. Furthermore, GM-CSF-treated groups showed higher mean fluorescence intensities (MFI) for critical markers such as MHC II and CD11c, with MFI levels surpassing those of SL-929-treated groups by approximately 3- to 5-fold. In contrast, the L-929 supernatant demonstrated limited efficacy in promoting both cell differentiation and surface marker expression, resulting in minimal phenotypic and quantitative gains compared to controls. These findings highlight the superior efficiency of GM-CSF in driving APC differentiation and underscore the importance of balancing cell yield and phenotypic fidelity when selecting differentiation protocols. This study provides valuable insights for researchers developing targeted immunotherapies and offers a solid foundation for optimizing APC-dependent therapies, ensuring efficacy and cost-efficiency in cell-based strategies. Full article
(This article belongs to the Section Molecular Immunology)
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22 pages, 3509 KB  
Article
Wedelia trilobata (L.) Leaf Extract Induces Autophagy-Mediated Cell Death in HT-29 Colorectal Cancer Cells via Suppression of the Akt/mTOR Signaling Axis
by Tue Minh Duong, Thanh Chau Quoc Nguyen, Tomonori Waku, Kenji Kanaori and Kaeko Kamei
Int. J. Mol. Sci. 2026, 27(10), 4636; https://doi.org/10.3390/ijms27104636 - 21 May 2026
Cited by 1 | Viewed by 748
Abstract
Colorectal cancer remains a global health challenge due to its high mortality and therapy resistance. While Wedelia trilobata (L.) (WT) exhibits pharmacological potential, its specific mechanisms against this cancer are not fully understood. We investigated the anticancer effects of W. trilobata leaf ethanol [...] Read more.
Colorectal cancer remains a global health challenge due to its high mortality and therapy resistance. While Wedelia trilobata (L.) (WT) exhibits pharmacological potential, its specific mechanisms against this cancer are not fully understood. We investigated the anticancer effects of W. trilobata leaf ethanol extract and its n-hexane and chloroform fractions on HT-29 cells. The WT extract significantly inhibited proliferation by inducing G1/S phase arrest and downregulating PCNA mRNA. It triggered substantial DNA damage (increased γ-H2AX) and suppressed the mitogen-activated protein kinase (ERK) pathway. Notably, the WT extract-induced autophagy-mediated cell death, marked by acidic vesicular organelle formation and increased LC3-II levels. Inhibition of autophagy with N-acetylcysteine and 3-methyladenine partially rescued cell viability, restored p-Akt levels, and reduced LC3-II, indicating that cell death is regulated via the ROS-mediated Akt/mTOR signaling axis. Additionally, autophagic flux was validated using chloroquine, which led to a synergistic accumulation of LC3-II. GC-MS analysis identified 48 and 52 compounds in the n-hexane and chloroform fractions, respectively, including metabolites with known antioxidant and antitumoral properties. These findings demonstrate that W. trilobata induces autophagic cell death through ROS-mediated Akt/mTOR inhibition, supporting its potential as a source of innovative colorectal cancer therapeutics. Full article
(This article belongs to the Section Biochemistry)
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35 pages, 2322 KB  
Review
The Molecular Mechanisms of Metformin’s Action on Blood Lipid Profile in Diabetic Patients
by Agnieszka Dettlaff-Pokora and Julian Swierczynski
Int. J. Mol. Sci. 2026, 27(10), 4635; https://doi.org/10.3390/ijms27104635 - 21 May 2026
Cited by 1 | Viewed by 1685
Abstract
In this paper, we review the literature regarding metformin’s action on blood lipid concentrations in metformin-treated diabetic patients. Published data indicate that metformin reduces serum total cholesterol (T-C), LDL-cholesterol (LDL-C) and triacylglycerol (TAG) concentrations and raises serum HDL-cholesterol (HDL-C) concentrations in diabetic patients. [...] Read more.
In this paper, we review the literature regarding metformin’s action on blood lipid concentrations in metformin-treated diabetic patients. Published data indicate that metformin reduces serum total cholesterol (T-C), LDL-cholesterol (LDL-C) and triacylglycerol (TAG) concentrations and raises serum HDL-cholesterol (HDL-C) concentrations in diabetic patients. The beneficial effect of metformin on serum lipid profiles in diabetic patients can result from (a) its action on AMP-activated protein kinase, which inhibits lipogenesis and cholesterol synthesis and stimulates fatty acid oxidation; (b) decreased plasma TAG concentrations, via promoting VLDL-TAG clearance by brown adipose tissue; (c) the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression, affecting lipid profile in diabetic patients; (d) the inhibition of the expression of genes encoding proprotein convertase subtilisin/kexin 9 (PCSK9) and lipogenic enzymes; (e) the downregulation of carbohydrate-response element-binding protein (ChREBP), which affects liver TAG and cholesterol synthesis from acetate formed by gut microbiota; (f) the inhibition of angiopoietin-like 3 protein (ANGPTL3) gene expression, and consequent effects on plasma TAG concentrations; (g) the activation of AMPK, which inhibits LXRα activity; and (h) reverse cholesterol transport. In conclusion, one can assume that beyond its primary antihyperglycemic effect, metformin exerts pleiotropic effects that modulate lipid metabolism and blood lipid profile in T2D patients. These beneficial effects of metformin on blood lipid profile may play a role in the reduction in cardiovascular risk in diabetic patients. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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23 pages, 3560 KB  
Review
Plant-Derived Bioactive Metabolites from the Sonoran Desert: Redox Regulation, Nrf2/NF-κB Signaling, and Emerging Therapeutic Applications
by Lidianys Maria Lewis-Luján, Annette Pulcherie Iloki-Lewis, Diego Emmanuel Guerrero-Magaña, Mikhail A. Osadchuk, Maxim V. Trushin, Juan Carlos Galvez-Ruiz, Judas Tadeo Vargas Durazo, Cinthia Jhovanna Perez-Martinez, Maria Guadalupe Burboa-Zazueta, Ana V. Torres-Figueroa, Sergio Trujillo Lopez and Simon Bernard Iloki-Assanga
Int. J. Mol. Sci. 2026, 27(10), 4634; https://doi.org/10.3390/ijms27104634 - 21 May 2026
Viewed by 607
Abstract
Plant-derived bioactive metabolites have emerged as promising modulators of oxidative stress and inflammation, two interconnected processes involved in the pathogenesis of numerous chronic diseases. Arid ecosystems, particularly the Sonoran Desert, constitute an underexplored source of structurally diverse phytochemicals with significant pharmacological potential. This [...] Read more.
Plant-derived bioactive metabolites have emerged as promising modulators of oxidative stress and inflammation, two interconnected processes involved in the pathogenesis of numerous chronic diseases. Arid ecosystems, particularly the Sonoran Desert, constitute an underexplored source of structurally diverse phytochemicals with significant pharmacological potential. This review provides a comprehensive overview of major classes of plant-derived bioactives, including polyphenols, flavonoids, terpenoids, and alkaloids, with emphasis on their molecular mechanisms of antioxidant and anti-inflammatory action. These compounds exert cytoprotective effects through direct reactive oxygen species (ROS) scavenging and indirect regulation of endogenous defense systems, primarily via activation of the Nrf2/Keap1 pathway and suppression of NF-κB signaling. Additional pathways, including MAPK, PI3K/Akt, AMPK, and mitochondrial regulatory networks, are discussed as critical mediators of redox balance and inflammatory control. Particular attention is given to Sonoran Desert plant species such as Bucida buceras, Phoradendron californicum, Larrea tridentata, Opuntia spp., and Agave deserti, all of which demonstrate promising biological activities associated with enhanced adaptation to environmental stress. Experimental approaches used to evaluate phytochemical bioactivity, including chemical assays, cellular models, omics technologies, and translational strategies, are also examined. Furthermore, this review discusses current limitations related to bioavailability, phytochemical variability, and clinical validation, highlighting emerging nanodelivery systems and precision medicine approaches as potential solutions. Collectively, the evidence supports the therapeutic relevance of Sonoran Desert plant bioactives as multi-target agents for modulating oxidative stress, inflammation, and chronic disease progression. Full article
(This article belongs to the Special Issue Plant-Origin Bioactive Substances)
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18 pages, 646 KB  
Review
CAFs and Endocrine Therapy Resistance in Hormone Receptor-Positive Breast Cancer
by Amalia A. Sofianidi, Vaia K. Stafyla and Flora Zagouri
Int. J. Mol. Sci. 2026, 27(10), 4633; https://doi.org/10.3390/ijms27104633 - 21 May 2026
Viewed by 934
Abstract
The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine [...] Read more.
The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone Receptors: Molecular Insights)
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22 pages, 4740 KB  
Article
Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer’s Disease Model
by Karin Wind-Mark, Lea H. Kunze, Michael Willem, Giovanna Palumbo, Camilla Giudici, Brigitte Nuscher, Guido Boening, Franz J. Gildehaus, Simon Lindner, Rudolf A. Werner, Nicolai Franzmeier, Johannes S. Gnörich, Matthias Brendel and Artem Zatcepin
Int. J. Mol. Sci. 2026, 27(10), 4632; https://doi.org/10.3390/ijms27104632 - 21 May 2026
Viewed by 893
Abstract
Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer’s disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic [...] Read more.
Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer’s disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. AppNL-G-F knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD. Full article
(This article belongs to the Special Issue Molecular Advances in Neuroimaging)
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11 pages, 1283 KB  
Case Report
Diagnosing Metformin Intoxication with High-Resolution Platelet Respirometry: A Case Report
by Ondřej Sobotka, Pavla Staňková, Joao Fortunato, Eva Trčková and Pavel Skořepa
Int. J. Mol. Sci. 2026, 27(10), 4631; https://doi.org/10.3390/ijms27104631 - 21 May 2026
Viewed by 705
Abstract
Metformin-associated lactic acidosis (MALA) involves mitochondrial Complex I inhibition, traditionally diagnosed via indirect markers. We present platelet high-resolution respirometry (HRR) as a novel “liquid biopsy” to directly quantify metformin-induced systemic bioenergetic lesions. A 65-year-old diabetic male presented with severe lactic acidosis, acute kidney [...] Read more.
Metformin-associated lactic acidosis (MALA) involves mitochondrial Complex I inhibition, traditionally diagnosed via indirect markers. We present platelet high-resolution respirometry (HRR) as a novel “liquid biopsy” to directly quantify metformin-induced systemic bioenergetic lesions. A 65-year-old diabetic male presented with severe lactic acidosis, acute kidney injury, and profound hypoglycemia after intentionally overdosing on metformin (120 g), dapagliflozin (600 mg), and insulin glargine (300 U). While hemodialysis cleared plasma metformin and resolved the acidosis, refractory hypoglycemia required high-dose IV glucose for over six days. Day 2 platelet HRR revealed severe Complex I inhibition despite significantly decreased plasma metformin, indicating a profound “toxicodynamic lag.” Mitochondrial bioenergetics recovered by Day 7, reflecting natural platelet turnover. The protracted hypoglycemia was driven by a synergistic triad: metformin-inhibited gluconeogenesis, insulin glargine’s prolonged depot effect, and dapagliflozin-induced persistent renal glucose wasting. Platelet HRR has the potential to be a clinically applicable tool to reveal the “hidden” cellular phase of metformin toxicity missed by standard biomarkers. Furthermore, clinicians must anticipate severe, protracted hypoglycemia in mixed overdoses involving SGLT2 inhibitors. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Disease: Mechanisms, Biomarkers and Emerging Therapies)
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24 pages, 590 KB  
Review
Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications
by Dimitris Liapopoulos, Panagiotis Sarantis, Georgios Zogas, Eleni-Myrto Trifylli, Thaleia-Eleftheria Bousou, Konstantina Kamitaki, Ioanna A. Anastasiou, Stefania Kokkali, Sotiris Mavromatis, Evangelos Koustas, Ioannis Elefsiniotis, Theodora Biniari and Michalis V. Karamouzis
Int. J. Mol. Sci. 2026, 27(10), 4630; https://doi.org/10.3390/ijms27104630 - 21 May 2026
Cited by 1 | Viewed by 1178
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1hi CD8+ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20–CCR6 and CCL22/CCL17–CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-β, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS+/CCR8+ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC. Full article
(This article belongs to the Special Issue Next-Gen Biomarkers for Cancer Immunotherapy)
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20 pages, 2413 KB  
Article
Protonation States of Proton-Sensing Glutamate Residues in Transporter Sialin
by Eric Wooten, Nara L. Chon, Muhamadjon Dzhalolov, Hongjin Zheng and Hai Lin
Int. J. Mol. Sci. 2026, 27(10), 4629; https://doi.org/10.3390/ijms27104629 - 21 May 2026
Viewed by 555
Abstract
Sialic acids are a diverse class of widely distributed monosaccharides that are engaged in a wide range of biological processes. Sialin, a sialic acid/proton symporter, transports sialic acid across membranes between the lysosomal lumen and cytosol, playing a critical role in sialin metabolism. [...] Read more.
Sialic acids are a diverse class of widely distributed monosaccharides that are engaged in a wide range of biological processes. Sialin, a sialic acid/proton symporter, transports sialic acid across membranes between the lysosomal lumen and cytosol, playing a critical role in sialin metabolism. Taking advantage of recently published experimental structures of sialin, we report here the first computational study that probes the molecular mechanism of ligand transport through sialin, which is yet to be fully understood. In particular, we carry out steered molecular dynamics simulations of the transport of N-acetylneuraminic acid, the most widely spread natural derivative of sialic acids, through sialin with two key glutamate residues (E171 and E175) in various protonation states. The previously proposed model is refined with enriched atomistic details from this study for the cotransport of sialic acid and proton. With additional quantum calculations, our data suggest a possible explanation for why mutation R168A retains most of the transport activities, but R168K does not. Full article
(This article belongs to the Special Issue Current Research in Membrane Transporters, Channels, and Receptors)
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30 pages, 1430 KB  
Review
Immune Checkpoint-Based Therapies in Colorectal Cancer—Current Approaches and Future Perspectives
by Katarzyna Nakielska, Jacek Plewka and Marzena Lenart
Int. J. Mol. Sci. 2026, 27(10), 4628; https://doi.org/10.3390/ijms27104628 - 21 May 2026
Cited by 2 | Viewed by 1103
Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune [...] Read more.
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune checkpoint pathways through the upregulation of inhibitory ligand expression within the tumor microenvironment, leading to lymphocyte exhaustion and impaired antitumor immunity. Consequently, immune checkpoints have emerged as important targets for immunotherapeutic intervention, with significant advances over the past decade. Nevertheless, despite demonstrated clinical benefits in selected patient subpopulations, the overall therapeutic efficacy of immune checkpoint inhibitors remains limited, particularly in the context of CRC. In this review, we provide a comprehensive overview of currently approved immune checkpoint-based immunotherapies for cancer treatment, with a specific focus on CRC, as well as ongoing clinical trials and evolving trends in this area. Furthermore, we discuss emerging targets and novel therapeutic strategies, with particular emphasis on innovative small-molecule inhibitors as potential alternatives to monoclonal antibody-based approaches. Finally, we outline future perspectives and potential directions for advancing immune checkpoint-targeted therapies in CRC. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer: 4th Edition)
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19 pages, 3308 KB  
Article
Effects of Inhaled Corticosteroids and Long-Acting β2-Agonists on Efferocytosis and Inflammatory Cell Survival: An In Vitro Study Relevant to COPD and Lung Cancer
by Bassam Redwan, Christian Biancosino, Stefan Fischer, Sabina Janciauskiene and Heiko Golpon
Int. J. Mol. Sci. 2026, 27(10), 4627; https://doi.org/10.3390/ijms27104627 - 21 May 2026
Viewed by 762
Abstract
Efferocytosis—the tightly regulated clearance of apoptotic cells by phagocytes—maintains tissue homeostasis and is impaired in chronic obstructive pulmonary disease (COPD), where it contributes to persistent inflammation and increases the risk of comorbidities, including lung cancer. Inhaled corticosteroids (ICS) and long-acting β2 agonists (LABAs) [...] Read more.
Efferocytosis—the tightly regulated clearance of apoptotic cells by phagocytes—maintains tissue homeostasis and is impaired in chronic obstructive pulmonary disease (COPD), where it contributes to persistent inflammation and increases the risk of comorbidities, including lung cancer. Inhaled corticosteroids (ICS) and long-acting β2 agonists (LABAs) are cornerstones of COPD therapy, but their effects on efferocytosis and on the COPD–lung cancer interface are incompletely understood. The primary objective of this study was to determine whether the ICS fluticasone propionate and the LABA salmeterol xinafoate, alone or in combination at clinically informed concentrations (10−8–10−6 M; 10−4 M reserved for cytotoxicity screening), modulate efferocytic capacity and inflammatory cell survival across diverse phagocyte models. We performed standardized in vitro efferocytosis assays using murine peritoneal and alveolar macrophages, the murine macrophage line J774A.1, PMA-differentiated human THP-1 macrophages, human blood-derived neutrophils, and the human alveolar adenocarcinoma cell line A549. Apoptosis was induced in Jurkat T cells by UV irradiation (100 mJ/cm2) and in murine thymocytes by dexamethasone (1 µM, 4 h); apoptotic and necrotic populations were characterized by annexin-V/propidium iodide and Sytox Green/Hoechst H-33342 staining. Peritoneal macrophages showed the highest efferocytic activity (~75%), followed by J774A.1 (~75% at 24 h), THP-1 (~30% at 2 h; ~60% at 24 h), alveolar macrophages (~40%), and A549 cells (<20%). Neither fluticasone nor salmeterol, individually or in combination, significantly altered efferocytic capacity in any phagocyte tested (all ANOVA p > 0.26). Fluticasone (10−8 and 10−6 M) significantly improved 24 h neutrophil survival and reduced early apoptosis (p < 0.05) but did not translate this survival benefit into enhanced efferocytosis. Salmeterol was cytotoxic at 10−4 M and inactive at 10−8–10−6 M. These findings indicate that the established anti-inflammatory benefits of ICS/LABA in COPD do not extend to augmentation of efferocytosis in this acute, serum-free in vitro setting and that pharmacological restoration of efferocytosis in COPD—a defect implicated in the pathogenesis and progression of comorbid lung cancer—will likely require strategies targeting the efferocytic machinery itself (e.g., MerTK, Rac-1, MFG-E8) rather than relying on current inhaled therapy. Full article
(This article belongs to the Special Issue Recent Advances in Lung Cancer)
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39 pages, 10608 KB  
Review
Mechanistic Insights into Dihydromyricetin: Redox Modulation and Kinase-Mediated Control of Disease Pathogenesis
by Oluwatoyin Adenike Fabiyi, Ayorinde Victor Ogundele, Sulyman Olalekan Ibrahim, Hassan Ibrahim and Héctor Hernán Silva
Int. J. Mol. Sci. 2026, 27(10), 4626; https://doi.org/10.3390/ijms27104626 - 21 May 2026
Cited by 1 | Viewed by 1064
Abstract
Dihydromyricetin (DHM), a naturally occurring flavanonol predominantly found in medicinal plants like Ampelopsis grossedentata, has emerged as a promising source of natural antioxidants with multi-target pharmacological activities relevant to drug discovery. DHM exhibits a strong redox-modulating capacity, effectively attenuating oxidative stress and [...] Read more.
Dihydromyricetin (DHM), a naturally occurring flavanonol predominantly found in medicinal plants like Ampelopsis grossedentata, has emerged as a promising source of natural antioxidants with multi-target pharmacological activities relevant to drug discovery. DHM exhibits a strong redox-modulating capacity, effectively attenuating oxidative stress and inflammation central drivers of chronic disease pathogenesis. Beyond direct radical scavenging, DHM regulates multiple redox-sensitive and kinase-mediated signalling pathways, thereby influencing key cellular processes involved in disease initiation and progression. This review synthesizes current evidence on the therapeutic potential of DHM, critically evaluating its mechanistic basis and translational prospects, with emphasis on its dual redox-driven and kinase-mediated modes of action. We detail its roles in metabolic disorders such as diabetes, obesity, and liver diseases, neuroprotection, cardio protection, and cancer prevention, focusing on the modulation of critical networks such as AMPK, PI3K/Akt, MAPK, NF-κB, and Nrf2. The interplay between these pathways underpins DHM’s efficacy across disease models. Furthermore, we highlight structure–activity relationship (SAR) analyses and molecular modelling studies that elucidate how the flavanonol scaffold, hydroxylation pattern, and stereochemistry of DHM govern its biological activities and target engagement. Key pharmacokinetic limitations, advances in extraction techniques, bioavailability challenges, and emerging formulation strategies including advanced delivery systems are discussed to address translational hurdles. Despite compelling preclinical data, the clinical translation of DHM remains constrained by limited human studies and incomplete mechanistic resolution. This review underscores the need for integrated pharmacological studies and innovative delivery approaches to translate the multifaceted promise of DHM into viable clinical interventions. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Potential of Natural Compounds)
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11 pages, 7200 KB  
Article
The Effective Biodegradation of Poly(ε-caprolactone) by Engineered Yeast Yarrowia lipolytica Producing Lipase B
by Żaneta Zdanowska, Lara Serrano-Aguirre, Aneta Krystyna Urbanek, Adam Dobrowolski and Aleksandra M. Mirończuk
Int. J. Mol. Sci. 2026, 27(10), 4625; https://doi.org/10.3390/ijms27104625 - 21 May 2026
Viewed by 477
Abstract
Poly(ε-caprolactone) (PCL) is a biodegradable aliphatic polyester with applications in many areas. Lipase B from Moesziomyces antarcticus (CALB, previously known as Candida antarctica lipase B) is a well-characterize enzyme capable of hydrolysing several polyesters. In this study, the codon-optimized gene encoding CALB was [...] Read more.
Poly(ε-caprolactone) (PCL) is a biodegradable aliphatic polyester with applications in many areas. Lipase B from Moesziomyces antarcticus (CALB, previously known as Candida antarctica lipase B) is a well-characterize enzyme capable of hydrolysing several polyesters. In this study, the codon-optimized gene encoding CALB was cloned into the yeast Yarrowia lipolytica to enhance its natural capabilities toward polyesters biodegradation. PCL films biodegradation was conducted directly in the medium using the engineered yeast at 28 °C. Process optimization employing baffled flasks significantly improved degradation efficiency and reduced time to 24 h. This study showed that the engineered yeast Y. lipolytica is a promising host for polyester biodegradation. Full article
(This article belongs to the Section Molecular Biophysics)
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29 pages, 4660 KB  
Article
Real-Life Metal Cocktail Induced Pancreatic Alterations in Rats: Influence of Sex and Exposure Duration
by Katarina Baralić, Đurđica Marić, Zorica Bulat, Danijela Đukić-Ćosić, Ivan Milošević, Anita Radovanović, Tijana Lužajić Božinovski, Vera Lukić, Aleksandra Repić, Biljana Antonijević and Aleksandra Buha Djordjevic
Int. J. Mol. Sci. 2026, 27(10), 4624; https://doi.org/10.3390/ijms27104624 - 21 May 2026
Viewed by 499
Abstract
Toxic metals from industrialization and urbanization pose major human health risks, and mixture-based exposure requires broader toxicity assessment. This study investigated the effects of a mixture of arsenic, lead, mercury, cadmium, chromium (VI), and nickel on pancreatic function in rats (45 male/45 female; [...] Read more.
Toxic metals from industrialization and urbanization pose major human health risks, and mixture-based exposure requires broader toxicity assessment. This study investigated the effects of a mixture of arsenic, lead, mercury, cadmium, chromium (VI), and nickel on pancreatic function in rats (45 male/45 female; n = 5 per group), focusing on sex- and duration-specific differences after 28 and 90 days of exposure. The metals were administered as a single mixture dissolved in deionised water via oral gavage. Evaluated parameters included pancreatic metal levels, histopathology, serum glucose, amylase, malate dehydrogenase 1 (MDH-1) activity, redox status, and bioelements. Dose levels were based on human exposure data to reflect realistic scenarios. Metals accumulated in pancreatic tissue, causing dose- and time-dependent histopathological changes, including acinar cell vacuolization, vascular congestion, and Langerhans islet alterations. Males showed more pronounced vascular and islet changes, while females had greater acinar alterations. In males, higher doses decreased glucose and amylase and increased MDH-1 activity, while females showed more variable responses. Males demonstrated adaptive responses to oxidative stress over time, while females experienced more persistent stress. These findings reveal sex-, dose-, and duration-dependent effects of toxic metal(oid) mixtures on pancreatic function, indicating that individually safe doses may be harmful when combined. Full article
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25 pages, 719 KB  
Review
Why Targeting Tumor Acidity Fails: Translational Barriers and Emerging Solutions
by Kyung-Hee Kim and Byong Chul Yoo
Int. J. Mol. Sci. 2026, 27(10), 4623; https://doi.org/10.3390/ijms27104623 - 21 May 2026
Viewed by 650
Abstract
Tumor acidity is a hallmark of the tumor microenvironment (TME) and has been widely regarded as a promising therapeutic target due to its ubiquity, functional relevance, and apparent selectivity for malignant tissues. Extensive preclinical studies have demonstrated that targeting tumor acidity—through inhibition of [...] Read more.
Tumor acidity is a hallmark of the tumor microenvironment (TME) and has been widely regarded as a promising therapeutic target due to its ubiquity, functional relevance, and apparent selectivity for malignant tissues. Extensive preclinical studies have demonstrated that targeting tumor acidity—through inhibition of lactate production, blockade of proton transport, systemic buffering, and pH-responsive drug delivery—can suppress tumor growth, reduce metastasis, and enhance antitumor immunity. However, despite strong mechanistic rationale and consistent preclinical efficacy, these strategies have failed to achieve meaningful and durable clinical success. In this review, we examine the underlying reasons for this translational discrepancy. We highlight key mechanistic and systemic barriers, including spatial heterogeneity of tumor pH, temporal dynamics and adaptive evolution, metabolic plasticity, redundancy of pH-regulating systems, systemic physiological constraints, and drug delivery limitations in hypoxic and acidic regions. We further argue that tumor acidity is not a sufficient standalone driver of tumor progression but rather a feature of a complex and adaptive system shaped by metabolic and microenvironmental interactions. Finally, we discuss emerging strategies that may overcome these limitations, including combination therapies integrating metabolic targeting with immunotherapy, pH-responsive drug delivery systems, microenvironment reprogramming, and biomarker-guided patient stratification. Overall, current evidence suggests that future therapeutic approaches may benefit more from exploiting tumor acidity as a feature of the tumor microenvironment rather than attempting to directly neutralize it. Full article
(This article belongs to the Special Issue Tumor Markers and Tumor Microenvironment)
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20 pages, 1055 KB  
Review
Targeting Microglia–Neuron Crosstalk to Regulate Neuronal Excitability: Novel Translational Approaches for Chronic Pain Intervention
by Zhenzhen Xu, Yong Lv, Shiqiang Chen and Qingping Wu
Int. J. Mol. Sci. 2026, 27(10), 4622; https://doi.org/10.3390/ijms27104622 - 21 May 2026
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Abstract
Chronic pain is a complex and widespread pathological state that severely impairs the quality of life of millions worldwide and imposes a heavy socioeconomic burden. Current therapeutic regimens often fail to provide adequate relief, frequently accompanied by dose-limiting side effects. Emerging evidence suggests [...] Read more.
Chronic pain is a complex and widespread pathological state that severely impairs the quality of life of millions worldwide and imposes a heavy socioeconomic burden. Current therapeutic regimens often fail to provide adequate relief, frequently accompanied by dose-limiting side effects. Emerging evidence suggests that the bidirectional crosstalk between microglia and neurons plays a fundamental role in the development and maintenance of chronic pain. This interaction contributes to central sensitization and enhanced neuronal excitability. This review elucidates the molecular mechanisms underlying microglia–neuron communication. with particular emphasis on its modulation of neuronal excitability. We also discuss innovative translational strategies such as gene therapy, cell therapy, and nanomedicine. Modulating these neuroimmune interfaces represents a promising frontier for developing more precise and efficacious analgesic interventions. Full article
(This article belongs to the Topic Research in Pharmacological Therapies, 2nd Edition)
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