International Journal of Molecular Sciences

17 pages, 4628 KiB

Open AccessArticle

Sea Anemone Kunitz Peptide HCIQ2c1 Reduces Histamine-, Lipopolysaccharide-, and Carrageenan-Induced Inflammation via the Suppression of Pro-Inflammatory Mediators

by Aleksandra N. Kvetkina, Anna A. Klimovich, Yulia V. Deriavko, Evgeniy A. Pislyagin, Ekaterina S. Menchinskaya, Evgenia P. Bystritskaya, Marina P. Isaeva, Ekaterina N. Lyukmanova, Zakhar O. Shenkarev, Dmitriy L. Aminin and Elena V. Leychenko

Int. J. Mol. Sci. 2025, 26(1), 431; https://doi.org/10.3390/ijms26010431 - 6 Jan 2025

Cited by 1 | Viewed by 1870

Abstract

Inflammation is a physiological response of the immune system to infectious agents or tissue injury, which involves a cascade of vascular and cellular events and the activation of biochemical pathways depending on the type of harmful agent and the stimulus generated. The Kunitz [...] Read more.

Inflammation is a physiological response of the immune system to infectious agents or tissue injury, which involves a cascade of vascular and cellular events and the activation of biochemical pathways depending on the type of harmful agent and the stimulus generated. The Kunitz peptide HCIQ2c1 of sea anemone Heteractis magnifica is a strong protease inhibitor and exhibits neuroprotective and analgesic activities. In this study, we investigated the anti-inflammatory potential of HCIQ2c1 in histamine- and lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as well as in LPS-induced systemic inflammation and carrageenan-induced paw edema models in CD-1 mice. We found that 10 μM HCIQ2c1 dramatically decreases histamine-induced intracellular Ca²⁺ release and LPS-induced reactive oxygen species (ROS) production in RAW 264.7 macrophages. Moreover, HCIQ2c1 significantly inhibited the production of LPS-induced tumor necrosis factor α (TNF-α), inducible NO-synthase (iNOS), and 5-lipoxygenase (5-LO) but slightly influenced the IL-1β and cyclooxygenase-2 (COX-2) expression level in macrophages. Furthermore, intravenous administration by HCIQ2c1 at 0.1 mg/kg dose reduced LPS-induced TNF-α, IL-1β, COX-2, and iNOS gene expression in CD-1 mice. The subplantar administration of HCIQ2c1 at 0.1 mg/kg dose to mice significantly reduced carrageenan-induced paw edema by a factor of two, which is comparable to the effect of diclofenac at 1 mg/kg dose. Thus, peptide HCIQ2c1 has a strong anti-inflammatory potential by the attenuation of systemic and local inflammatory effects through the inhibition of intracellular Ca²⁺ release, the production of ROS and pro-inflammatory cytokines, and enzymes involved in arachidonic acid metabolism. Full article

(This article belongs to the Special Issue The Structures and Biologic Activity of Marine Natural Products)

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25 pages, 8782 KiB

Open AccessArticle

Chronic Exposure to Two Regimens of Waterpipe Smoke Elicits Lung Injury, Genotoxicity, and Mitochondrial Impairment with the Involvement of MAPKs Activation in Mice

by Naserddine Hamadi, Suhail Al-Salam, Sumaya Beegam, Nur Elena Zaaba, Ozaz Elzaki and Abderrahim Nemmar

Int. J. Mol. Sci. 2025, 26(1), 430; https://doi.org/10.3390/ijms26010430 - 6 Jan 2025

Viewed by 1444

Abstract

While the pulmonary effects of regular waterpipe smoking (R-WPS) are well-defined, the impact of occasional waterpipe smoking (O-WPS) on the lungs remains less established. This study investigated the pulmonary toxicity and underlying mechanisms of O-WPS versus R-WPS following 6 months of exposure, focusing [...] Read more.

While the pulmonary effects of regular waterpipe smoking (R-WPS) are well-defined, the impact of occasional waterpipe smoking (O-WPS) on the lungs remains less established. This study investigated the pulmonary toxicity and underlying mechanisms of O-WPS versus R-WPS following 6 months of exposure, focusing on histopathology, inflammation in the lung, bronchoalveolar lavage fluid (BALF), and plasma, as well as oxidative stress, genotoxicity, mitochondrial dysfunction, and the expression of mitogen-activated protein kinases (MAPKs) in lung homogenates. Exposure to both O-WPS and R-WPS resulted in significant histological changes, including increased numbers of alveolar macrophages and lymphocytes, as well as interstitial fibrosis. Only R-WPS increased the number of neutrophil polymorphs and plasma cells. R-WPS also significantly increased the chemokines CXCL1, CXCL2, and CCL2 in the lung, BALF, and plasma, while O-WPS increased CXCL1 and CXCL2 in the lung and CXCL1 in the plasma. Both exposure regimens significantly increased lung injury markers, including matrix metalloproteinase-9 and myeloperoxidase. Additionally, R-WPS induced a significant increase in the cytokines IL1β, IL6, and TNFα in the lung, BALF, and plasma, while O-WPS elevated IL1β and IL6 in the lung. Oxidative stress was observed, with increased levels of thiobarbituric acid reactive substances and superoxide dismutase in both the O-WPS and R-WPS groups. Exposure to either O-WPS or R-WPS triggered genotoxicity and altered mitochondrial complex activities. R-WPS exposure also resulted in elevated expression of p-JNK/JNK, p-ERK/ERK, and p-p38/p38, while O-WPS augmented the p-ERK/ERK ratio in the lungs. Taken together, these findings indicate that both O-WPS and R-WPS contribute to lung injury and induce inflammation, oxidative stress, genotoxicity, and mitochondrial dysfunction, with R-WPS having a more pronounced effect. These effects were associated with the activation of MAPKs. Full article

(This article belongs to the Special Issue Environmental Pollutants and Lung Diseases: Cellular and Molecular Mechanisms)

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17 pages, 3869 KiB

Open AccessArticle

Goose Deoxycholic Acid Ameliorates Liver Injury in Laying Hens with Fatty Liver Hemorrhage Syndrome by Inhibiting the Inflammatory Response

by Nannan Wang, Weiwei Li, Guangyi Ouyang, Hengqi Li, Jiancheng Yang and Gaofeng Wu

Int. J. Mol. Sci. 2025, 26(1), 429; https://doi.org/10.3390/ijms26010429 - 6 Jan 2025

Viewed by 1283

Abstract

Fatty liver hemorrhagic syndrome (FLHS) in laying hens is a nutritional and metabolic disease involving liver enlargement, hepatic steatosis, and hepatic hemorrhage as the primary symptoms. The syndrome is prone to occur during the peak laying period of laying hens, which has resulted [...] Read more.

Fatty liver hemorrhagic syndrome (FLHS) in laying hens is a nutritional and metabolic disease involving liver enlargement, hepatic steatosis, and hepatic hemorrhage as the primary symptoms. The syndrome is prone to occur during the peak laying period of laying hens, which has resulted in significant economic losses in the laying hen breeding industry; however, the specific pathogenesis of FLHS remains unclear. Our group and previous studies have shown that bile acid levels are significantly decreased during the development of fatty liver and that targeted activation of bile acid–related signaling pathways is beneficial for preventing and treating fatty liver. In this study, we generated a FLHS laying hen model by feeding hens a high-energy, low-protein diet, with goose deoxycholic acid (CDCA) given as an intervention. HE staining, fluorescence quantitative PCR, and ELISA were used to evaluate the effects of CDCA on pathological changes and inflammatory responses in the liver. The results showed that hepatic hemorrhage in FLHS laying hens was reduced after CDCA treatment. Furthermore, fat vacuoles and transaminase levels decreased significantly. In addition, expression levels of M1-type macrophage markers and polarization products were significantly reduced, and the expression of pro-inflammatory regulatory factors related to the JAK-STAT signaling pathway, LPS-TLR4-Myd88–NF-kB signaling pathway, and NLRP3 inflammasomes decreased significantly as well. Expression levels of M2-type macrophage markers and polarization products increased significantly, as did the expression of anti-inflammatory regulators related to the JAK-STAT signaling pathway. These results suggest that CDCA ameliorates liver injury in laying hens with FLHS by inhibiting macrophage M1-type polarization and the resulting pro-inflammatory response, thereby promoting M2-type macrophage polarization and an anti-inflammatory response. Full article

(This article belongs to the Section Molecular Immunology)

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24 pages, 5258 KiB

Open AccessArticle

CD8+ and CD8− NK Cells and Immune Checkpoint Networks in Peripheral Blood During Healthy Pregnancy

by Matyas Meggyes, David U. Nagy, Livia Mezosi, Beata Polgar and Laszlo Szereday

Int. J. Mol. Sci. 2025, 26(1), 428; https://doi.org/10.3390/ijms26010428 - 6 Jan 2025

Viewed by 1191

Abstract

Pregnancy involves significant immunological changes to support fetal development while protecting the mother from infections. A growing body of evidence supports the importance of immune checkpoint pathways, especially at the maternal–fetal interface, although limited information is available about the peripheral expression of these [...] Read more.

Pregnancy involves significant immunological changes to support fetal development while protecting the mother from infections. A growing body of evidence supports the importance of immune checkpoint pathways, especially at the maternal–fetal interface, although limited information is available about the peripheral expression of these molecules by CD8+ and CD8− NK cell subsets during the trimesters of pregnancy. Understanding the dynamics of these immune cells and their checkpoint pathways is crucial for elucidating their roles in pregnancy maintenance and potential complications. This study aims to investigate the peripheral expression and functional characteristics of CD8+ and CD8− NK cell subsets throughout pregnancy, providing insights into their contributions to maternal and fetal health. A total of 34 healthy women were enrolled from the first, 30 from the second and 40 from the third trimester of pregnancy. At the same time, 35 healthy age-matched non-pregnant women formed the control group. From peripheral blood, mononuclear cells were separated and stored at −80 °C. CD8+ and CD8− NK cell subsets were analyzed from freshly thawed samples, and surface and intracellular staining was performed using flow cytometric analyses. The proportions of CD56+ NK cells in peripheral blood were similar across groups. While CD8− NKdim cells increased significantly in all trimesters compared to non-pregnant controls, CD8+ NKdim cells showed no significant changes. CD8− NKbright cells had higher frequencies throughout pregnancy, whereas CD8+ NKbright cells significantly increased only in the first and second trimesters. The expression levels of immune checkpoint molecules, such as PD-1 and PD-L1, and cytotoxic-activity-related molecules were stable, with notable perforin and granzyme B increases in CD8− NKbright cells throughout pregnancy. Our study shows that peripheral NK cell populations, especially CD8− subsets, are predominant during pregnancy. This shift suggests a crucial role for CD8− NK cells in balancing maternal immune tolerance and surveillance. The stable expression of immune checkpoint molecules indicates that other regulatory mechanisms may be at work. These findings enhance our understanding of peripheral immune dynamics in pregnancy and suggest that targeting CD8− NKbright cell functions could help manage pregnancy-related immune complications. This research elucidates the stable distribution and functional characteristics of peripheral NK cells during pregnancy, with CD8− subsets being more prevalent. The increased activity of CD8− NKbright cells suggests their critical role in maintaining immune surveillance. Our findings provide a basis for future studies to uncover the mechanisms regulating NK cell function in pregnancy, potentially leading to new treatments for immune-related pregnancy complications. Full article

(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology, 2nd Edition)

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26 pages, 5602 KiB

Open AccessArticle

Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells

by Juan De los Santos-Jiménez, José A. Campos-Sandoval, Tracy Rosales, Bookyung Ko, Francisco J. Alonso, Javier Márquez, Ralph J. DeBerardinis and José M. Matés

Int. J. Mol. Sci. 2025, 26(1), 427; https://doi.org/10.3390/ijms26010427 - 6 Jan 2025

Cited by 1 | Viewed by 1333

Abstract

Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor. Glioblastoma cells [...] Read more.

Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor. Glioblastoma cells usually lack GLS2 while they express high GLS. We investigated how GLS2 expression modifies the metabolism of glioblastoma cells, looking for changes that may explain GLS2’s potential tumour suppressive role. We developed LN-229 glioblastoma cells stably expressing GLS2 and performed isotope tracing using U-¹³C-glutamine and metabolomic quantification to analyze metabolic changes. Treatment with GLS inhibitor CB-839 was also included to concomitantly inhibit endogenous GLS. GLS2 overexpression resulted in extensive metabolic changes, altering the TCA cycle by upregulating part of the cycle but blocking the synthesis of the 6-carbon intermediates from acetyl-CoA. Expression of GLS2 caused downregulation of PDH activity through phosphorylation of S293 of PDHA1. GLS2 also altered nucleotide levels and induced the accumulation of methylated metabolites and S-adenosyl methionine. These changes suggest that GLS2 may be a key regulator linking glutamine and glucose metabolism, also impacting nucleotides and epigenetics. Future research should ascertain the mechanisms involved and the generalizability of these findings in cancer or physiological conditions. Full article

(This article belongs to the Special Issue Targeting Glioblastoma Metabolism)

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21 pages, 6192 KiB

Open AccessArticle

Anti-Tumor Effects of Sheep Umbilical Cord Mesenchymal Stem Cells on Melanoma Cells

by Fengjiao Yue, Yuqing Zhao, Yiting Lv, Songmei Li, Weihai Wang, Yajun Li, Shujie Wang and Chunsheng Wang

Int. J. Mol. Sci. 2025, 26(1), 426; https://doi.org/10.3390/ijms26010426 - 6 Jan 2025

Viewed by 1333

Abstract

Melanoma is among the most common malignancies and has recently exhibited increased resistance to treatments, resulting in a more aggressive disease course. Mesenchymal stem cells (MSCs) secrete cytokines both in vivo and in vitro, which regulate tumor cell signaling pathways and the tumor [...] Read more.

Melanoma is among the most common malignancies and has recently exhibited increased resistance to treatments, resulting in a more aggressive disease course. Mesenchymal stem cells (MSCs) secrete cytokines both in vivo and in vitro, which regulate tumor cell signaling pathways and the tumor microenvironment, thereby influencing tumor progression. This study investigates the anti-melanogenesis effects of sheep umbilical cord mesenchymal stem cells (SUCMSCs) to assess their potential application in melanoma treatment. Our findings indicate that, in vitro, SUCMSCs reduce melanin content and tyrosinase activity, inhibit melanoma cell viability, proliferation, migration, and invasion, and promote melanoma cell apoptosis. Subsequent in vivo experiments confirmed that SUCMSCs effectively suppress tumor growth, and histological analysis via HE staining revealed notable differences. Additionally, transcriptome sequencing analysis indicated that the anti-tumor effects were primarily mediated through autophagy, apoptosis, and the TGF-β and NF-κB signaling pathways. The RT-qPCR validation results aligned with the transcriptome data. In summary, SUCMSCs exert anti-melanogenesis effects through the interaction of multiple signaling pathways and cytokines, demonstrating significant potential for melanoma treatment. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 262 KiB

Open AccessArticle

Whole-Exome Sequencing: Discovering Genetic Causes of Granulomatous Mastitis

by Beyza Ozcinar, Zeynep Ocak, Deryanaz Billur, Baris Ertugrul and Ozlem Timirci-Kahraman

Int. J. Mol. Sci. 2025, 26(1), 425; https://doi.org/10.3390/ijms26010425 - 6 Jan 2025

Viewed by 1134

Abstract

Granulomatous mastitis (GM) is a rare, benign, but chronic and recurrent inflammatory breast disease that significantly impacts physical and psychological well-being. It often presents symptoms such as pain, swelling, and discharge, leading to diagnostic confusion with malignancy. The etiology of GM remains unclear, [...] Read more.

Granulomatous mastitis (GM) is a rare, benign, but chronic and recurrent inflammatory breast disease that significantly impacts physical and psychological well-being. It often presents symptoms such as pain, swelling, and discharge, leading to diagnostic confusion with malignancy. The etiology of GM remains unclear, though autoimmune and multifactorial components are suspected. This study aimed to explore the genetic underpinnings of GM using whole-exome sequencing (WES) on 22 GM patients and 52 healthy controls to identify single nucleotide variants (SNVs) and copy number variations (CNVs) potentially linked to the disease. WES analysis revealed novel SNVs in six genes: BRCA2 (rs169547), CFTR (rs4727853), NCF1 (rs10614), PTPN22 (rs2476601), HLA-DRB1 (seven variants), and C3 (rs406514). Notably, most of these variants are associated with immune regulation and inflammatory pathways, supporting the hypothesis that GM is an autoimmune disease. However, all identified variants were classified as benign according to the American College of Medical Genetics and Genomics (ACMG) guidelines, necessitating further investigation into their potential functional effects. Despite conducting CNV analysis, no significant variations were identified. This study represents a foundational step in linking genetic predisposition to GM and highlights the need for integrating genetic, clinical, and functional data to better understand GM’s pathophysiology. Future research should focus on larger cohorts, functional studies, and exploring multifactorial contributors to GM, including hormonal and environmental factors. Full article

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

15 pages, 3372 KiB

Open AccessArticle

Identification of Endometriosis Pathophysiologic-Related Genes Based on Meta-Analysis and Bayesian Approach

by Jieun Kang, Kwangjin Ahn, Jiyeon Oh, Taesic Lee, Sangwon Hwang, Young Uh and Seong Jin Choi

Int. J. Mol. Sci. 2025, 26(1), 424; https://doi.org/10.3390/ijms26010424 - 6 Jan 2025

Viewed by 1169

Abstract

Endometriosis is a complex disease with diverse etiologies, including hormonal, immunological, and environmental factors; however, its exact pathogenesis remains unknown. While surgical approaches are the diagnostic and therapeutic gold standard, identifying endometriosis-associated genes is a crucial first step. Five endometriosis-related gene expression studies [...] Read more.

Endometriosis is a complex disease with diverse etiologies, including hormonal, immunological, and environmental factors; however, its exact pathogenesis remains unknown. While surgical approaches are the diagnostic and therapeutic gold standard, identifying endometriosis-associated genes is a crucial first step. Five endometriosis-related gene expression studies were selected from the available datasets. Approximately, 14,167 genes common to these 5 datasets were analyzed for differential expression. Meta-analyses utilized fold-change values and standard errors obtained from each analysis, with the binomial and continuous datasets contributing to endometriosis presence and endometriosis severity meta-analysis, respectively. Approximately 160 genes showed significant results in both meta-analyses. For Bayesian analysis, endometriosis-related single nucleotide polymorphisms (SNPs), the human transcription factor catalog, uterine SNP-related gene expression, disease–gene databases, and interactome databases were utilized. Twenty-four genes, present in at least three or more databases, were identified. Network analysis based on Pearson’s correlation coefficients revealed the HLA-DQB1 gene with both a high score in the Bayesian analysis and a central position in the network. Although ZNF24 had a lower score, it occupied a central position in the network, followed by other ZNF family members. Bayesian analysis identified genes with high confidence that could support discovering key diagnostic biomarkers and therapeutic targets for endometriosis. Full article

(This article belongs to the Special Issue Computer Analysis for Molecular Pathological Research)

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20 pages, 3448 KiB

Open AccessArticle

Homeodomain Involvement in Nuclear HOX Protein Homo- and Heterodimerization

by Damien Marchese, Laetitia Evrard, Isabelle Bergiers, Ludovic Boas, Justine Duphénieux, Maryse Hermant, Tamara Pringels, Fisnik Zeqiri, Marc Pirson, Jean-Claude Twizere, Françoise Gofflot, René Rezsohazy and Laure Bridoux

Int. J. Mol. Sci. 2025, 26(1), 423; https://doi.org/10.3390/ijms26010423 - 6 Jan 2025

Viewed by 3019

Abstract

HOX genes play essential roles in patterning the anteroposterior axis of animal embryos and in the formation of various organs. In mammals, there are 39 HOX genes organized into four clusters (HOXA–D) located on different chromosomes. In relationship with their orderly arrangement along [...] Read more.

HOX genes play essential roles in patterning the anteroposterior axis of animal embryos and in the formation of various organs. In mammals, there are 39 HOX genes organized into four clusters (HOXA–D) located on different chromosomes. In relationship with their orderly arrangement along the chromosomes, these genes show nested expression patterns which imply that embryonic territories co-express multiple HOX genes along the main body axis. Interactomic database entries, as well as a handful of publications, support that some HOX proteins can form homodimers or interact with other HOX proteins. However, the consequences of HOX protein interactions have been poorly investigated and remain largely elusive. In this study, we compiled a repository of all HOX–HOX interactions from available databases, and taking HOXA1, HOXA2, and HOXA5 as examples, we investigated the capacity of HOX proteins to form homo- and heterodimers. We revealed that while the DNA-binding domain, the homeodomain, is not necessary for HOXA1 homodimerization, the nuclear localization of the dimerization is dependent on the homeodomain, particularly the integrity of the third helix of HOXA1. Furthermore, we demonstrated that HOXA1 can influence the localization of HOXA1 when it is deprived of the homeodomain, increasing its abundance in the chromatin-containing fraction. Moreover, HOXA1 nuclear homodimerization occurs independently of the integrity of the hexapeptide and, consequently, of its well-known interactor, the homeodomain protein PBX. These results hint at a potential involvement of dimerization in the complex landscape of HOX regulatory mechanisms. Full article

(This article belongs to the Special Issue Biomolecular Basis of Life Processes)

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16 pages, 5203 KiB

Open AccessArticle

Ligand-Independent Vitamin D Receptor Actions Essential for Keratinocyte Homeostasis in the Skin

by Satoko Kise, Shinichi Morita, Toshiyuki Sakaki, Hiroyuki Kimura, Seigo Kinuya and Kaori Yasuda

Int. J. Mol. Sci. 2025, 26(1), 422; https://doi.org/10.3390/ijms26010422 - 6 Jan 2025

Cited by 1 | Viewed by 1230

Abstract

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the [...] Read more.

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since Vdr-KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among Vdr-KO, Vdr-R270L/H301Q, and wild-type (WT) rats. While Vdr-R270L/H301Q rats exhibited normal skin formation similar to WT rats, Vdr-KO rats showed remarkable hyperkeratosis and trans-epidermal water loss in the skin. RNA sequencing and proteomic analysis revealed that the gene and protein expression patterns in Vdr-KO rats significantly differed from those in WT and Vdr-R270L/H301Q rats, with a marked decrease in the expression of factors involved in Shh, Wnt, and Bmp signaling pathways, a dramatic reduction in the expression of hair keratins, and a substantial increase in the expression of epidermal keratins. This study clearly demonstrated that non-liganded VDR is significantly involved in the differentiation, proliferation, and cell death of keratinocytes in hair follicles and the epidermis. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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23 pages, 5187 KiB

Open AccessArticle

Single and Combined Impact of Semaglutide, Tirzepatide, and Metformin on β-Cell Maintenance and Function Under High-Glucose–High-Lipid Conditions: A Comparative Study

by Esmaeel Ghasemi Gojani, Bo Wang, Dongping Li, Olga Kovalchuk and Igor Kovalchuk

Int. J. Mol. Sci. 2025, 26(1), 421; https://doi.org/10.3390/ijms26010421 - 6 Jan 2025

Viewed by 2019

Abstract

Type 2 diabetes (T2D), the most common form, is marked by insulin resistance and β-cell failure. β-cell dysfunction under high-glucose–high-lipid (HG-HL) conditions is a key contributor to the progression of T2D. This study evaluates the comparative effects of 10 nM semaglutide, 10 nM [...] Read more.

Type 2 diabetes (T2D), the most common form, is marked by insulin resistance and β-cell failure. β-cell dysfunction under high-glucose–high-lipid (HG-HL) conditions is a key contributor to the progression of T2D. This study evaluates the comparative effects of 10 nM semaglutide, 10 nM tirzepatide, and 1 mM metformin, both alone and in combination, on INS-1 β-cell maintenance and function under HG-HL conditions. INS-1 cells were pretreated for 2 h with single doses of metformin (1 mM), semaglutide (10 nM), tirzepatide (10 nM), or combinations of 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide, followed by 48 h of HG-HL stimulation. The results indicate that combining 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide significantly enhances the effects of 10 nM semaglutide and 10 nM tirzepatide on HG-HL-induced apoptosis and dysregulated cell cycle. Specifically, the combination treatments demonstrated superior restoration of glucose-stimulated insulin secretion (GSIS) functionality compared to 1 mM metformin, 10 nM semaglutide, and 10 nM tirzepatide. Full article

(This article belongs to the Special Issue The Effect of Natural Products on Obesity, Aging, and Longevity)

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15 pages, 1269 KiB

Open AccessReview

The Fetal Environment and the Development of Hypertension—The Epigenetic Modification by Glucocorticoids

by Fumiko-Kawakami Mori and Tatsuo Shimosawa

Int. J. Mol. Sci. 2025, 26(1), 420; https://doi.org/10.3390/ijms26010420 - 6 Jan 2025

Cited by 2 | Viewed by 1474

Abstract

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure [...] Read more.

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure to GCs continues to affect not only intrauterine fetal development itself, but also the metabolic status and neural activity in adulthood through epigenetic changes such as microRNA change, histone modification, and DNA methylation. We have shown that the IUGR model induced DNA hypomethylation in the paraventricular nucleus (PVN) in the brain, which in turn activates sympathetic activities, the renin–angiotensin system (RAS), contributing to the development of salt-sensitive hypertension. Even in adulthood, strong stress and/or exogenous steroids have been shown to induce epigenetic changes in the brain. Furthermore, DNA hypomethylation in the PVN is also observed in other hypertensive rat models, which suggests that it contributes significantly to the origins of elevated blood pressure. These findings suggest that if we can alter epigenetic changes in the brain, we can treat or prevent hypertension. Full article

(This article belongs to the Special Issue Advances and Challenges of Molecular Research on Disease in Animal Models in Biomedicine)

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12 pages, 1065 KiB

Open AccessArticle

The Role of Exercise-Based Cardiac Rehabilitation After Myocardial Infarction on Cholesterol Transfer to HDL

by Jose C. Nicolau, Talia F. Dalcoquio, Roberto R. Giraldez, Fatima R. Freitas, Andre M. Nicolau, Remo H. M. Furtado, Thauany M. Tavoni, Luciano M. Baracioli, Felipe G. Lima, Aline G. Ferrari, Maria U. P. B. Rondon, Rocio Salsoso, Maria J. N. N. Alves, Flavia B. B. Arantes, Mayara A. Santos, Leandro S. Alves, Carlos E. Negrao and Raul C. Maranhão

Int. J. Mol. Sci. 2025, 26(1), 419; https://doi.org/10.3390/ijms26010419 - 6 Jan 2025

Cited by 1 | Viewed by 1228

Abstract

High-density lipoprotein (HDL) is associated with decreased incidence of cardiovascular events, and its functionality also influences prognosis. Exercise is an important tool to improve prognosis in the post-infarction (MI) population, but the role of exercise on HDL functionality is poorly understood. Sixty-two patients [...] Read more.

High-density lipoprotein (HDL) is associated with decreased incidence of cardiovascular events, and its functionality also influences prognosis. Exercise is an important tool to improve prognosis in the post-infarction (MI) population, but the role of exercise on HDL functionality is poorly understood. Sixty-two patients with acute MI were randomized in a supervised exercise program for 12–14 weeks (exercise group—EG) or a control group (CG). The main objective of the study was to analyze the role of exercise on esterified cholesterol (EC) and unesterified cholesterol (UC) transfer to HDL. For the total population, the baseline mean rate of EC transfer to HDL was 2.53 ± 0.83 and at the end of follow-up, it was 2.74 ± 0.64 (p = 0.03). The figures for UC were, respectively, 4.08 ± 1.2 and 4.4 ± 1.06 (p = 0.02). The difference (follow-up minus baseline) for EC was 0.15 ± 0.84 for the control group and 0.27 ± 0.69 for the exercise group (p = 0.53); for UC, the figures were 0.28 ± 1.14 and 0.35 ± 0.96 (p = 0.80), respectively, for the control and exercise groups. In post-MI patients, 12–14 weeks of supervised exercise did not improve HDL functionality. Full article

(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health)

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14 pages, 11896 KiB

Open AccessArticle

Genome-Wide Identification and Functional Characterization of SKP1-like Gene Family Reveal Its Involvement in Response to Stress in Cotton

by Zhao Geng, Jianguang Liu, Guiyuan Zhao, Xiangli Geng, Xu Liu, Xingyu Liu, Hanshuang Zhang and Yongqiang Wang

Int. J. Mol. Sci. 2025, 26(1), 418; https://doi.org/10.3390/ijms26010418 - 6 Jan 2025

Viewed by 890

Abstract

SKP1 constitutes the Skp1-Cullin-F-box ubiquitin E3 ligase (SCF), which plays a role in plant growth and development and biotic and abiotic stress in ubiquitination. However, the response of the SKP1-like gene family to abiotic and biotic stresses in cotton has not been well [...] Read more.

SKP1 constitutes the Skp1-Cullin-F-box ubiquitin E3 ligase (SCF), which plays a role in plant growth and development and biotic and abiotic stress in ubiquitination. However, the response of the SKP1-like gene family to abiotic and biotic stresses in cotton has not been well characterized. In this study, a total of 72 SKP1-like genes with the conserved domain of SKP1 were identified in four Gossypium species. Synteny and collinearity analyses revealed that segmental duplication played a major role in the expansion of the cotton SKP1-like gene family. All SKP1-like proteins were classified into three different subfamilies via phylogenetic analysis. Furthermore, we focused on a comprehensive analysis of SKP1-like genes in G. hirsutum. The cis-acting elements in the promoter site of the GhSKP1-like genes predict their involvement in multiple hormonal and defense stress responses. The expression patterns results indicated that 16 GhSKP1-like genes were expressed in response to biotic or abiotic stresses. To further validate the role of the GhSKP1-like genes in salt stress, four GhSKP1-like genes were randomly selected for gene silencing via VIGS. The results showed that the silencing of GhSKP1-like_7A resulted in the inhibition of plant growth under salt stress, suggesting that GhSKP1-like_7A was involved in the response to salt stress. In addition, yeast two-hybrid results revealed that GhSKP1-like proteins have different abilities to interact with F-box proteins. These results provide valuable information for elucidating the evolutionary relationships of the SKP1-like gene family and aiding further studies on the function of SKP1-like genes in cotton. Full article

(This article belongs to the Section Molecular Plant Sciences)

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20 pages, 7409 KiB

Open AccessArticle

Proteomic Profile of Daphnia pulex in Response to Heavy Metal Pollution in Lakes of Northern Patagonia

by Juan-Alejandro Norambuena, Patricia Poblete-Grant, Jorge F. Beltrán, Patricio De los Ríos-Escalante, Cristian Aranzaez-Ríos and Jorge G. Farías

Int. J. Mol. Sci. 2025, 26(1), 417; https://doi.org/10.3390/ijms26010417 - 6 Jan 2025

Viewed by 893

Abstract

Over recent decades, Northern Patagonia in Chile has seen significant growth in agriculture, livestock, forestry, and aquaculture, disrupting lake ecosystems and threatening native species. These environmental changes offer a chance to explore how anthropization impacts zooplankton communities from a molecular–ecological perspective. This study [...] Read more.

Over recent decades, Northern Patagonia in Chile has seen significant growth in agriculture, livestock, forestry, and aquaculture, disrupting lake ecosystems and threatening native species. These environmental changes offer a chance to explore how anthropization impacts zooplankton communities from a molecular–ecological perspective. This study assessed the anthropogenic impact on Daphnia pulex by comparing its proteomes from two lakes: Llanquihue (anthropized) and Icalma (oligotrophic). Results showed substantial differences in protein expression, with 17 proteins upregulated and 181 downregulated in Llanquihue, linked to elevated levels of copper, manganese, dissolved solids, phosphate, and nitrogen. These stressors caused metabolic damage and environmental stress in D. pulex. Our findings highlight the importance of monitoring pollution’s effects on Northern Patagonian ecosystems, especially on keystone species like D. pulex, essential for ecosystem stability. This research provides fresh molecular–ecological insights into pollution’s impacts, a perspective rarely addressed in this region. Understanding these effects is critical for conserving natural resources and offers pathways to study adaptive mechanisms in keystone species facing pollution. This approach also informs strategies for ecosystem management and restoration, addressing both immediate and long-term challenges in Northern Patagonian aquatic environments. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Biology in Chile, 2nd Edition)

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16 pages, 3631 KiB

Open AccessArticle

Metal Ion Supplementation to Boost Melanin Production by Streptomyces nashvillensis

by Odile Francesca Restaino, Talayeh Kordjazi, Francesco Tancredi, Paola Manini, Fabiana Lanzillo, Francesca Raganati, Antonio Marzocchella, Raffaele Porta and Loredana Mariniello

Int. J. Mol. Sci. 2025, 26(1), 416; https://doi.org/10.3390/ijms26010416 - 6 Jan 2025

Cited by 1 | Viewed by 815

Abstract

As Streptomycetes might produce melanin to survive in stressful environmental conditions, like under metal exposure, supplementing metal ions to the growth medium could be a wise strategy for boosting the production of the pigment. The aim of this study was to test, for [...] Read more.

As Streptomycetes might produce melanin to survive in stressful environmental conditions, like under metal exposure, supplementing metal ions to the growth medium could be a wise strategy for boosting the production of the pigment. The aim of this study was to test, for the first time, the possibility of boosting S. nashvillensis DSM40314 melanin biosynthesis by adding to the growth medium singularly or, at the same time, different concentrations (1.0, 1.5, and 2.0 g∙L⁻¹) of CuSO₄ or/and Fe₂(SO₄)₃. A maximum melanin production of 4.0 ± 0.1 g·L⁻¹ was obtained in shake flasks with a 2.0 g∙L⁻¹ coupled addition of the two metals, while the extracellular tyrosinase activities ranged values between 5.4 and 11.6 ± 0.1 U·L⁻¹. The pigments produced in different conditions were precipitated from the broth supernatants under acidic conditions, purified, and characterized by UV-VIS, FT-IR, and NMR analyses that determined structures like eumelanin pigments. Fermentation experiments in stirred tank reactors allowed to scale up the process in more controlled conditions, further boosting the pigment production up to 4.9 ± 0.1 g·L⁻¹, with an increase of about 22.0% compared to the results obtained in shake flasks. Full article

(This article belongs to the Special Issue Melanin and Other Pigments: Function, Synthesis and Characterization)

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18 pages, 1483 KiB

Open AccessReview

Dual Roles of miR-10a-5p and miR-10b-5p as Tumor Suppressors and Oncogenes in Diverse Cancers

by Rajan Singh, Se Eun Ha, Tae Yang Yu and Seungil Ro

Int. J. Mol. Sci. 2025, 26(1), 415; https://doi.org/10.3390/ijms26010415 - 6 Jan 2025

Cited by 1 | Viewed by 1346

Abstract

Cancer is a complex genetic disorder characterized by abnormalities in both coding and regulatory non-coding RNAs. microRNAs (miRNAs) are key regulatory non-coding RNAs that modulate cancer development, functioning as both tumor suppressors and oncogenes. miRNAs play critical roles in cancer progression, influencing key [...] Read more.

Cancer is a complex genetic disorder characterized by abnormalities in both coding and regulatory non-coding RNAs. microRNAs (miRNAs) are key regulatory non-coding RNAs that modulate cancer development, functioning as both tumor suppressors and oncogenes. miRNAs play critical roles in cancer progression, influencing key processes such as initiation, promotion, and metastasis. They exert their effects by targeting tumor suppressor genes, thereby facilitating cancer progression, while also inhibiting oncogenes to prevent further disease advancement. The miR-10 family, particularly miR-10a-5p and miR-10b-5p (miR-10a/b-5p), is notably involved in cancer progression. Intriguingly, their functions can differ across different cancers, sometimes promoting and at other times suppressing tumor growth depending on the cancer type and target genes. This review explores the dual roles of miR-10a/b-5p as tumor-suppressive miRNAs (TSmiRs) or oncogenic miRNAs (oncomiRs) in various cancers by examining their molecular and cellular mechanisms and their impact on the tumor microenvironment. Furthermore, we discuss the potential of miR-10a/b-5p as therapeutic targets, emphasizing miRNA-based strategies for cancer treatment. The insights discussed in this review aim to advance our understanding of miR-10a/b-5p’s roles in tumor biology and their application in developing innovative cancer therapies. Full article

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

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16 pages, 3943 KiB

Open AccessArticle

Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading

by Ksenia A. Zaripova, Svetlana P. Belova, Tatiana Y. Kostrominova, Boris S. Shenkman and Tatiana L. Nemirovskaya

Int. J. Mol. Sci. 2025, 26(1), 414; https://doi.org/10.3390/ijms26010414 - 6 Jan 2025

Viewed by 778

Abstract

During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca²⁺ to enter the nucleus through IP3 receptors. This may contribute to the activation of [...] Read more.

During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca²⁺ to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca²⁺-dependent signaling pathways by reducing the mRNA expression of the Ca²⁺-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy. Full article

(This article belongs to the Special Issue Molecular Insight into Skeletal Muscle Atrophy and Regeneration)

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34 pages, 2675 KiB

Open AccessReview

Chronic Gastrointestinal Disorders and miRNA-Associated Disease: An Up-to-Date

by Alessandro Giammona, Bruno Giovanni Galuzzi, Elena Imperia, Clarissa Gervasoni, Sofia Remedia, Laura Restaneo, Martina Nespoli, Laura De Gara, Flaminia Tani, Michele Cicala, Michele Pier Luca Guarino, Danilo Porro, Antonio Cerasa, Alessia Lo Dico, Annamaria Altomare and Gloria Bertoli

Int. J. Mol. Sci. 2025, 26(1), 413; https://doi.org/10.3390/ijms26010413 - 6 Jan 2025

Cited by 1 | Viewed by 1869

Abstract

Chronic gastrointestinal disorders such as inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS) impose significant health burdens globally. IBDs, encompassing Crohn’s disease and ulcerative colitis, are multifactorial disorders characterized by chronic inflammation of the gastrointestinal tract. On the other hand, IBS is [...] Read more.

Chronic gastrointestinal disorders such as inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS) impose significant health burdens globally. IBDs, encompassing Crohn’s disease and ulcerative colitis, are multifactorial disorders characterized by chronic inflammation of the gastrointestinal tract. On the other hand, IBS is one of the principal gastrointestinal tract functional disorders and is characterized by abdominal pain and altered bowel habits. Although the precise etiopathogenesis of these disorders remains unclear, mounting evidence suggests that non-coding RNA molecules play crucial roles in regulating gene expression associated with inflammation, apoptosis, oxidative stress, and tissue permeability, thus influencing disease progression. miRNAs have emerged as possible reliable biomarkers, as they can be analyzed in the biological fluids of patients at a low cost. This review explores the roles of miRNAs in IBDs and IBS, focusing on their involvement in the control of disease hallmarks. By an extensive literature review and employing bioinformatics tools, we identified the miRNAs frequently studied concerning these diseases. Ultimately, specific miRNAs could be proposed as diagnostic biomarkers for IBDs and IBS. Their ability to be secreted into biofluids makes them promising candidates for non-invasive diagnostic tools. Therefore, understanding molecular mechanisms through the ways in which they regulate gastrointestinal inflammation and immune responses could provide new insights into the pathogenesis of IBDs and IBS and open avenues for miRNA-based therapeutic interventions. Full article

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

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25 pages, 13314 KiB

Open AccessArticle

Study on the Chemical Composition and Multidrug Resistance Reversal Activity of Euphorbia uralensis (Euphorbiaceae)

by Yina Ding, Yuhao Liu, Qianru Dang, Zubair Akram, Anam Arshad, Haochan Zhu, Jianxiang Zhang, Bo Han and Chimengul Turghun

Int. J. Mol. Sci. 2025, 26(1), 412; https://doi.org/10.3390/ijms26010412 - 6 Jan 2025

Viewed by 902

Abstract

Euphorbia uralensis belongs to the family Euphorbiaceae and is widely distributed in northern Xinjiang, making it a characteristic plant of the region in Xinjiang, China. The chemical composition and biological activity of Euphorbia uralensis have not yet been reported, although certain compounds isolated [...] Read more.

Euphorbia uralensis belongs to the family Euphorbiaceae and is widely distributed in northern Xinjiang, making it a characteristic plant of the region in Xinjiang, China. The chemical composition and biological activity of Euphorbia uralensis have not yet been reported, although certain compounds isolated from Euphorbia plants in Xinjiang, China, have demonstrated exceptional multidrug resistance (MDR) reversal. This study aims to investigate the chemical components present in Euphorbia uralensis with the potential to reverse MDR. The aerial parts of Euphorbia uralensis were extracted using organic solvents of varying polarities, resulting in dichloromethane (Fr-E) and petroleum ether (Fr-S) fractions, which exhibited greater MDR reversal activity than the other fractions. The chemical constituents of the Fr-S fraction were analyzed using GC-MS. The chemical components of the Fr-E fraction were isolated and purified using column chromatography. The most effective compounds with MDR reversal activity were screened out, and the mechanism was investigated using molecular docking, molecular dynamics simulations, Western blotting, and rhodamine 123 staining. GC-MS analysis showed that the Fr-S fraction was rich in triterpenes, fatty acids, phenols, and long-chain alkanes, all of which were identified for the first time in Euphorbia uralensis. Among these, palmitic acid was present at a content level of 15.86%. This study notably unveils the discovery of a new compound and 16 previously recorded compounds for the first time in this plant, with the main types identified as steroids, sesquiterpenes, and flavonoids. The isolated compounds were tested for cytotoxicity and MDR reversal activity. The new compounds Euphouralosides A, pubinernoid A, naringenin, and punigratine showed good MDR reversal activity against MCF-7 and MCF-7/ADR cell lines. Punigratine was the most active compound. Moreover, punigratine could stably bind to the ABCB1 protein. Western blot analysis revealed that punigratine did not affect the expression of the ABCB1 protein in cells (p > 0.05). However, following treatment with punigratine (0.16 μM), there was a significant increase the intracellular accumulation of Rh123 in MCF-7/ADR cells (p < 0.05). These findings suggest that punigratine can inhibit the efflux of the ABCB1 protein, thereby overcoming MDR in tumors. This study provides a foundation for further research on the biological activity and medicinal potential of Euphorbia uralensis. Full article

(This article belongs to the Section Molecular Pharmacology)

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2 pages, 5189 KiB

Open AccessCorrection

Correction: Tian et al. Genome-Wide Identification of the DnaJ Gene Family in Citrus and Functional Characterization of ClDJC24 in Response to Citrus Huanglongbing. Int. J. Mol. Sci. 2024, 25, 11967

by Yuzhen Tian, Xizi Wang, Huoqing Huang, Xin Deng, Baihong Zhang, Yixuan Meng, Libo Wu, Hang Chen, Yun Zhong and Wenli Chen

Int. J. Mol. Sci. 2025, 26(1), 411; https://doi.org/10.3390/ijms26010411 - 6 Jan 2025

Viewed by 673

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Genetic Engineering of Plants for Stress Tolerance)

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20 pages, 3995 KiB

Open AccessReview

A New Strategy in Modulating the Protease-Activated Receptor 2 (Par2) in Autoimmune Diseases

by Lynn Khoon and Ron Piran

Int. J. Mol. Sci. 2025, 26(1), 410; https://doi.org/10.3390/ijms26010410 - 6 Jan 2025

Cited by 1 | Viewed by 1356

Abstract

Autoimmune diseases are complex conditions characterized by immune-mediated tissue damage and chronic inflammation. Protease-activated receptor 2 (Par2) has been implicated in these diseases, exhibiting dual roles that complicate its therapeutic potential. This review examines the perplexing functions of Par2, which promotes inflammation through [...] Read more.

Autoimmune diseases are complex conditions characterized by immune-mediated tissue damage and chronic inflammation. Protease-activated receptor 2 (Par2) has been implicated in these diseases, exhibiting dual roles that complicate its therapeutic potential. This review examines the perplexing functions of Par2, which promotes inflammation through immune cell activation while facilitating tissue healing in damaged organs. By analyzing findings across diverse autoimmune conditions, including rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease, we highlight how the context and location of Par2 activation determine its effects. Recent studies from our laboratory have resolved some of these contradictions by distinguishing Par2’s immune-mediated inflammatory roles from its tissue-reparative functions. These insights pave the way for context-specific therapeutic strategies, such as selective Par2 modulators, that can mitigate inflammation while enhancing tissue repair. However, achieving such precision in modulation remains a significant challenge, necessitating further research into Par2’s signaling pathways. This review underscores Par2’s complexity and its transformative potential in autoimmune disease management, offering a nuanced perspective on its duality and therapeutic implications. Full article

(This article belongs to the Special Issue Molecular Aspects of Autoimmune Diseases)

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17 pages, 11911 KiB

Open AccessArticle

Cooperative and Independent Functionality of tmRNA and SmpB in Aeromonas veronii: A Multifunctional Exploration Beyond Ribosome Rescue

by Taipeng Bai, Juanjuan Li, Xue Chi, Hong Li, Yanqiong Tang, Zhu Liu and Xiang Ma

Int. J. Mol. Sci. 2025, 26(1), 409; https://doi.org/10.3390/ijms26010409 - 6 Jan 2025

Viewed by 812

Abstract

The trans-translation system, mediated by transfer-messenger RNA (tmRNA, encoded by the ssrA gene) and its partner protein SmpB, helps to release ribosomes stalled on defective mRNA and targets incomplete protein products for hydrolysis. Knocking out the ssrA and smpB genes in various pathogens [...] Read more.

The trans-translation system, mediated by transfer-messenger RNA (tmRNA, encoded by the ssrA gene) and its partner protein SmpB, helps to release ribosomes stalled on defective mRNA and targets incomplete protein products for hydrolysis. Knocking out the ssrA and smpB genes in various pathogens leads to different phenotypic changes, indicating that they have both cooperative and independent functionalities. This study aimed to clarify the functional relationships between tmRNA and SmpB in Aeromonas veronii, a pathogen that poses threats in aquaculture and human health. We characterized the expression dynamics of the ssrA and smpB genes at different growth stages of the pathogen, assessed the responses of deletion strains ΔssrA and ΔsmpB to various environmental stressors and carbon source supplementations, and identified the gene-regulatory networks involving both genes by integrating transcriptomic and phenotypic analyses. Our results showed that the gene ssrA maintained stable expression throughout the bacterial growth period, while smpB exhibited upregulated expression in response to nutrient deficiencies. Compared to the wild type, both the ΔssrA and ΔsmpB strains exhibited attenuated resistance to most stress conditions. However, ΔssrA independently responded to starvation, while ΔsmpB specifically showed reduced resistance to lower concentrations of Fe³⁺ and higher concentrations of Na⁺ ions, as well as increased utilization of the carbon source β-Methyl-D-glucoside. The transcriptomic analysis supported these phenotypic results, demonstrating that tmRNA and SmpB cooperate under nutrient-deficient conditions but operate independently in nutrient-rich environments. Phenotypic experiments confirmed that SsrA and SmpB collaboratively regulate genes involved in siderophore synthesis and iron uptake systems in response to extracellular iron deficiency. The findings of the present study provide crucial insights into the functions of the trans-translation system and highlight new roles for tmRNA and SmpB beyond trans-translation. Full article

(This article belongs to the Section Molecular Biology)

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4 pages, 7839 KiB

Open AccessCorrection

Correction: Abou-ElNaga et al. Novel Nano-Therapeutic Approach Actively Targets Human Ovarian Cancer Stem Cells after Xenograft into Nude Mice. Int. J. Mol. Sci. 2017, 18, 813

by Amoura Abou-ElNaga, Ghada Mutawa, Ibrahim M. El-Sherbiny, Hassan Abd-ElGhaffar, Ahmed A. Allam, Jamaan Ajarem and Shaker A. Mousa

Int. J. Mol. Sci. 2025, 26(1), 408; https://doi.org/10.3390/ijms26010408 - 6 Jan 2025

Viewed by 674

Abstract

In the original publication [...] Full article

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

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40 pages, 2342 KiB

Open AccessReview

Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense

by Pauline Pöpperl, Melanie Stoff and Andreas Beineke

Int. J. Mol. Sci. 2025, 26(1), 407; https://doi.org/10.3390/ijms26010407 - 5 Jan 2025

Cited by 1 | Viewed by 2698

Abstract

Respiratory viral infections continue to cause pandemic and epidemic outbreaks in humans and animals. Under steady-state conditions, alveolar macrophages (AlvMϕ) fulfill a multitude of tasks in order to maintain tissue homeostasis. Due to their anatomic localization within the deep lung, AlvMϕ are prone [...] Read more.

Respiratory viral infections continue to cause pandemic and epidemic outbreaks in humans and animals. Under steady-state conditions, alveolar macrophages (AlvMϕ) fulfill a multitude of tasks in order to maintain tissue homeostasis. Due to their anatomic localization within the deep lung, AlvMϕ are prone to detect and react to inhaled viruses and thus play a role in the early pathogenesis of several respiratory viral infections. Here, detection of viral pathogens causes diverse antiviral and proinflammatory reactions. This fact not only makes them promising research targets, but also suggests them as potential targets for therapeutic and prophylactic approaches. This review aims to give a comprehensive overview of the current knowledge about the role of AlvMϕ in respiratory viral infections of humans and animals. Full article

(This article belongs to the Special Issue Viral Diseases of the Respiratory System—Molecular Mechanisms and Pathogenesis 2.0)

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25 pages, 3942 KiB

Open AccessReview

Pathophysiology and Management Strategies for Post-Stroke Spasticity: An Update Review

by Bei Chen, Tong Yang, Zi Liao, Feiyue Sun, Zhigang Mei and Wenli Zhang

Int. J. Mol. Sci. 2025, 26(1), 406; https://doi.org/10.3390/ijms26010406 - 5 Jan 2025

Cited by 2 | Viewed by 3782

Abstract

Post-stroke spasticity (PSS), characterized by a velocity-dependent increase in muscle tone and exaggerated reflexes, affects a significant portion of stroke patients and presents a substantial obstacle to post-stroke rehabilitation. Effective management and treatment for PSS remains a significant clinical challenge in the interdisciplinary [...] Read more.

Post-stroke spasticity (PSS), characterized by a velocity-dependent increase in muscle tone and exaggerated reflexes, affects a significant portion of stroke patients and presents a substantial obstacle to post-stroke rehabilitation. Effective management and treatment for PSS remains a significant clinical challenge in the interdisciplinary aspect depending on the understanding of its etiologies and pathophysiology. We systematically review the relevant literature and provide the main pathogenic hypotheses: alterations in the balance of excitatory and inhibitory inputs to the descending pathway or the spinal circuit, which are secondary to cortical and subcortical ischemic or hemorrhagic injury, lead to disinhibition of the stretch reflex and increased muscle tone. Prolongation of motoneuron responses to synaptic excitation by persistent inward currents and secondary changes in muscle contribute to hypertonia. The guidelines for PSS treatment advocate for a variety of therapeutic approaches, yet they are hindered by constraints such as dose-dependent adverse effects, high cost, and limited therapeutic efficacy. Taken together, we highlight key processes of PSS pathophysiology and summarize many interventions, including neuroprotective agents, gene therapy, targeted therapy, physiotherapy, NexTGen therapy and complementary and alternative medicine. We aim to confer additional clinical benefits to patients and lay the foundation for the development of new potential therapies against PSS. Full article

(This article belongs to the Special Issue CNS Injuries: 2nd Edition)

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18 pages, 4635 KiB

Open AccessArticle

Lactoferrin Attenuates Pro-Inflammatory Response and Promotes the Conversion into Neuronal Lineages in the Astrocytes

by Melania Ruggiero, Antonia Cianciulli, Rosa Calvello, Dario Domenico Lofrumento, Concetta Saponaro, Francesca Martina Filannino, Chiara Porro and Maria Antonietta Panaro

Int. J. Mol. Sci. 2025, 26(1), 405; https://doi.org/10.3390/ijms26010405 - 5 Jan 2025

Viewed by 1317

Abstract

Neurodegenerative diseases are characterized by progressive loss of neurons and persistent inflammation. Neurons are terminally differentiated cells, and lost neurons cannot be replaced since neurogenesis is restricted to only two neurogenic niches in the adult brain, whose neurogenic potential decreases with age. In [...] Read more.

Neurodegenerative diseases are characterized by progressive loss of neurons and persistent inflammation. Neurons are terminally differentiated cells, and lost neurons cannot be replaced since neurogenesis is restricted to only two neurogenic niches in the adult brain, whose neurogenic potential decreases with age. In this regard, the astrocytes reprogramming into neurons may represent a promising strategy for restoring the lost neurons and rebuilding neural circuits. To date, many anti-inflammatory agents have been shown to reduce neuroinflammation; however, their potential to restore neuronal loss was poorly investigated. This study investigates the anti-inflammatory effects of lactoferrin on DI-TNC1 astrocyte cell line and its ability to induce astrocyte reprogramming in a context of sustained inflammation. For this purpose, astrocytes were pre-treated with lactoferrin (4 μg/mL) for 24 h, then with lipopolysaccharide (LPS) (400 ng/mL), and examined 2, 9 and 16 days from treatment. The results demonstrate that lactoferrin attenuates astrocyte reactivity by reducing Toll-like receptor 4 (TLR4), Glial fibrillary acidic protein (GFAP) and IL-6 expression, as well as by upregulating Interleukin-10 (IL-10) cytokine and NRF2 expression. Moreover, lactoferrin promotes the reprogramming of reactive astrocytes into proliferative neuroblasts by inducing the overexpression of the Sex determining region Y/SRY-box 2 (SOX2) reprogramming transcription factor. Overall, this study highlights the potential effects of lactoferrin to attenuate neuroinflammation and improve neurogenesis, suggesting a future strategy for the treatment of neurodegenerative disorders. Full article

(This article belongs to the Section Molecular Neurobiology)

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25 pages, 5977 KiB

Open AccessArticle

Theoretical Study of Antioxidant and Prooxidant Potency of Protocatechuic Aldehyde

by Ana Amić, Denisa Mastiľák Cagardová and Žiko Milanović

Int. J. Mol. Sci. 2025, 26(1), 404; https://doi.org/10.3390/ijms26010404 - 5 Jan 2025

Cited by 2 | Viewed by 1006

Abstract

In this study, the antioxidant and prooxidant potency of protocatechuic aldehyde (PCA) was evaluated using density functional theory (DFT). The potency of direct scavenging of hydroperoxyl (HOO^•) and lipid peroxyl radicals (modeled by vinyl peroxyl, H₂C=CHOO^•) involved [...] Read more.

In this study, the antioxidant and prooxidant potency of protocatechuic aldehyde (PCA) was evaluated using density functional theory (DFT). The potency of direct scavenging of hydroperoxyl (HOO^•) and lipid peroxyl radicals (modeled by vinyl peroxyl, H₂C=CHOO^•) involved in lipid peroxidation was estimated. The repair of oxidative damage in biomolecules (lipids, proteins and nucleic acids) and the prooxidant ability of PCA phenoxyl radicals were considered. The repairing potency of PCA was investigated for damaged tryptophan, cysteine, leucine, DNA base guanine and linolenic acid. The thermodynamics and kinetics of the single electron transfer (SET) and formal hydrogen atom transfer (fHAT) mechanisms underlying the studied processes were investigated under physiological conditions in aqueous and lipid environments using the SMD/M06-2X/6-311++G(d,p) level of theory. Sequestration of catalytic Fe²⁺ and Fe³⁺ ions by PCA, which prevents HO^• production via Fenton-like reactions, was modeled. Molecular docking was used to study the inhibitory capability of PCA against xanthine oxidase (XO), one of the enzymes producing reactive oxygen species. The attained results show that PCA has the capability to scavenge lipid peroxyl radicals, repair damaged tryptophan, leucine and guanine, chelate catalytic iron ions and inhibit XO. Thus, PCA could be considered a possible multifunctional antioxidant. Full article

(This article belongs to the Special Issue Density Functional Theory for Rational Drug Design and the Prediction of Natural Compounds’ Bioactivity)

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35 pages, 3838 KiB

Open AccessReview

Roles of the Receptor for Advanced Glycation End Products and Its Ligands in the Pathogenesis of Alzheimer’s Disease

by Wen Li, Qiuping Chen, Chengjie Peng, Dan Yang, Si Liu, Yanwen Lv, Langqi Jiang, Shijun Xu and Lihua Huang

Int. J. Mol. Sci. 2025, 26(1), 403; https://doi.org/10.3390/ijms26010403 - 5 Jan 2025

Cited by 1 | Viewed by 1682

Abstract

The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer’s disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), [...] Read more.

The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer’s disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain’s ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE’s significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials. Full article

(This article belongs to the Special Issue Abnormal Organelles and Protein Expression in Acute and Chronic Neurodegeneration)

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26 pages, 880 KiB

Open AccessReview

Diffuse Noxious Inhibitory Controls in Chronic Pain States: Insights from Pre-Clinical Studies

by Raquel Pereira-Silva, Fani L. Neto and Isabel Martins

Int. J. Mol. Sci. 2025, 26(1), 402; https://doi.org/10.3390/ijms26010402 - 5 Jan 2025

Viewed by 1077

Abstract

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement [...] Read more.

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement of several neurochemical systems in DNIC/CPM and point to a major contribution of the noradrenergic, serotonergic, and opioidergic systems. Here, we thoroughly review the latest data on the monoaminergic and opioidergic studies, focusing particularly on pre-clinical models of chronic pain. We also conduct an in-depth analysis of these systems by integrating the available data with the descending pain modulatory circuits and the neurochemical systems therein to bring light to the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic effects but also hyperalgesic effects. This duality might be explained by the underlying circuitry and the receptor subtypes involved therein. Acknowledging this duality might contribute to validating the prognostic nature of the paradigm. Additionally, DNIC/CPM may serve as a robust paradigm with predictive value for guiding pain treatment through more effective targeting of descending pain modulation. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Chronic Pain)

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Int. J. Mol. Sci., Volume 26, Issue 1 (January-1 2025) – 431 articles

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