International Journal of Molecular Sciences

24 pages, 1184 KB

Open AccessArticle

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

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)

25 pages, 821 KB

Open AccessReview

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

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)

41 pages, 1339 KB

Open AccessReview

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

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)

18 pages, 3163 KB

Open AccessArticle

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

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)

15 pages, 2084 KB

Open AccessArticle

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 (registering DOI) - 21 May 2026

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)

13 pages, 925 KB

Open AccessArticle

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

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)

12 pages, 828 KB

Open AccessArticle

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

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)

12 pages, 961 KB

Open AccessArticle

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

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

Open AccessReview

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

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

Open AccessArticle

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

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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20 pages, 3037 KB

Open AccessArticle

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

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)

13 pages, 7012 KB

Open AccessBrief 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

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

Open AccessArticle

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

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

Open AccessBrief 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

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

Open AccessArticle

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

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, 1708 KB

Open AccessReview

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

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)

24 pages, 3284 KB

Open AccessReview

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

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)

18 pages, 646 KB

Open AccessReview

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

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, 5508 KB

Open AccessArticle

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

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. App^NL-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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