Journal Description
International Journal of Molecular Sciences
International Journal of Molecular Sciences
is an international, peer-reviewed, open access journal providing an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, and is published semimonthly online by MDPI. The Australian Society of Plant Scientists (ASPS), Epigenetics Society, European Calcium Society (ECS), European Chitin Society (EUCHIS), Spanish Society for Cell Biology (SEBC) and others are affiliated with IJMS and their members receive a discount on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, MEDLINE, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Biochemistry & Molecular Biology) / CiteScore - Q1 (Inorganic Chemistry)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16.3 days after submission; acceptance to publication is undertaken in 2.6 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Testimonials: See what our editors and authors say about the IJMS.
- Companion journals for IJMS include: Biophysica, Obesities, Stresses and Lymphatics.
Impact Factor:
5.6 (2022);
5-Year Impact Factor:
6.2 (2022)
Latest Articles
Effect of Donor Age on Endocrine Function of and Immune Response to Ovarian Grafts
Int. J. Mol. Sci. 2024, 25(6), 3431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063431 (registering DOI) - 19 Mar 2024
Abstract
Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only
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Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6–8 (D7) or 20–22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic–pituitary–ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection.
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(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)
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Chemical Constituents of Stinging Nettle (Urtica dioica L.): A Comprehensive Review on Phenolic and Polyphenolic Compounds and Their Bioactivity
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Saša Đurović, Ivan Kojić, Danka Radić, Yulia A. Smyatskaya, Julia G. Bazarnova, Snežana Filip and Tomislav Tosti
Int. J. Mol. Sci. 2024, 25(6), 3430; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063430 (registering DOI) - 18 Mar 2024
Abstract
Polyphenolic compounds are of great interest in today’s science. Naturally, they occur in plants and other sources in many different forms. Their wide range of biological activity has attracted the attention of the scientific community. One of the sources of phenolic compounds is
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Polyphenolic compounds are of great interest in today’s science. Naturally, they occur in plants and other sources in many different forms. Their wide range of biological activity has attracted the attention of the scientific community. One of the sources of phenolic compounds is stinging nettle (Urtica dioica L.), a common plant in almost all parts of the world. A long tradition of utilization and an interesting chemical profile make this plant a fascinating and extensive object of study. The chemical profile also allows this plant to be used as a food and a pigment source in the food, pharmaceutical, and cosmetic industries. Previously conducted studies found phenolic acids and polyphenolic compounds in root, stalk, and stinging nettle leaves. Different extraction techniques were usually used to isolate them from the leaves. Obtained extracts were used to investigate biological activity further or formulate different functional food products. This study aimed to collect all available knowledge about this plant, its chemical composition, and biological activity and to summarize this knowledge with particular attention to polyphenolic compounds and the activity and mechanisms of their actions.
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(This article belongs to the Special Issue Polyphenols and Their Transformation Products: Properties and Mechanism of Action)
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Open AccessArticle
Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology
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Diána Simon, Dorottya Kacsándi, Anita Pusztai, Boglárka Soós, Edit Végh, György Kerekes, Monika Bodoki, Szilvia Szamosi, Gabriella Szűcs, Zoltán Prohászka, Péter Németh, Tímea Berki and Zoltán Szekanecz
Int. J. Mol. Sci. 2024, 25(6), 3429; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063429 (registering DOI) - 18 Mar 2024
Abstract
Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on
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Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs.
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(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)
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Open AccessArticle
Tumor-Targeted Squaraine Dye for Near-Infrared Fluorescence-Guided Photodynamic Therapy
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Yoonbin Park, Min Ho Park and Hoon Hyun
Int. J. Mol. Sci. 2024, 25(6), 3428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063428 - 18 Mar 2024
Abstract
Many efforts have been made to develop near-infrared (NIR) fluorescent dyes with high efficiency for the NIR laser-induced phototherapy of cancer. However, the low tumor targetability and high nonspecific tissue uptake of NIR dyes in vivo limit their applications in preclinical cancer imaging
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Many efforts have been made to develop near-infrared (NIR) fluorescent dyes with high efficiency for the NIR laser-induced phototherapy of cancer. However, the low tumor targetability and high nonspecific tissue uptake of NIR dyes in vivo limit their applications in preclinical cancer imaging and therapy. Among the various NIR dyes, squaraine (SQ) dyes are widely used due to their high molar extinction coefficient, intense fluorescence, and excellent photostability. Previously, benzoindole-derived SQ (BSQ) was prepared by incorporating carboxypentyl benzoindolium end groups into a classical SQ backbone, followed by conjugating with cyclic RGD peptides for tumor-targeted imaging. In this study, we demonstrate that the structure-inherent tumor-targeting BSQ not only shows a high fluorescence quantum yield in serum but also exhibits superior reactive oxygen species (ROS) generation capability under the 671 nm laser irradiation for effective photodynamic therapy (PDT) in vitro and in vivo. Without targeting ligands, the BSQ was preferentially accumulated in tumor tissue 24 h post-injection, which was the optimal timing of the laser irradiation to induce increments of ROS production. Therefore, this work provides a promising strategy for the development of photodynamic therapeutic SQ dyes for targeted cancer therapy.
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(This article belongs to the Special Issue Molecular Aspects of Photodynamic Therapy)
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Open AccessArticle
Domestication Gene Mlx and Its Partner Mondo Are Involved in Controlling the Larval Body Size and Cocoon Shell Weight of Bombyx mori
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Xiaoxuan Qin, Liang Jiang, Ping Zhao, Ying Lin, Yi Zhang and Qingyou Xia
Int. J. Mol. Sci. 2024, 25(6), 3427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063427 - 18 Mar 2024
Abstract
Bombyx mori was domesticated from Bombyx mandarina. The long-term domestication of the silkworm has brought about many remarkable changes to its body size and cocoon shell weight. However, the molecular mechanism underlying the improvement in the economic characteristics of this species during
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Bombyx mori was domesticated from Bombyx mandarina. The long-term domestication of the silkworm has brought about many remarkable changes to its body size and cocoon shell weight. However, the molecular mechanism underlying the improvement in the economic characteristics of this species during domestication remains unclear. In this study, we found that a transposable element (TE)—Bm1—was present in the upstream regulatory region of the Mlx (Max-like protein X) gene in wild silkworms but not in all domesticated silkworms. The absence of Bm1 caused an increase in the promoter activity and mRNA content of Mlx. Mlx and its partner Mondo belong to the bHLHZ transcription factors family and regulate nutrient metabolism. RNAi of Mlx and Mondo decreased the expression and promoter activity of glucose metabolism-related genes (trehalose transport (Tret), phosphofructokinase (PFK), and pyruvate kinase (PK)), lipogenic genes (Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)), and glutamine synthesis gene (Glutamine synthase 2, (GS2)). Furthermore, the transgenic overexpression of Mlx and Mondo in the fat body of silkworms increased the larval body size, cocoon shell weight, and egg number, but the silencing of the two genes resulted in the opposite phenotypes. Our results reveal the molecular mechanism of Mlx selection during domestication and its successful use in the molecular breeding of Bombyx mori.
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(This article belongs to the Special Issue Adipose Tissue and Gene Expression)
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Mesenchymal Stromal Cells Derived from Canine Adipose Tissue: Evaluation of the Effect of Different Shipping Vehicles Used for Clinical Administration
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Valentina Andreoli, Priscilla Berni, Virna Conti, Roberto Ramoni, Giuseppina Basini and Stefano Grolli
Int. J. Mol. Sci. 2024, 25(6), 3426; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063426 - 18 Mar 2024
Abstract
Mesenchymal Stromal Cells (MSCs)-based therapies are rapidly gaining interest in veterinary medicine. Cellular therapy represents a new challenge for practitioners and requires precise coordination between the cell processing laboratory and the veterinary clinic. Cryopreservation is the best method to provide fast, in-time, and
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Mesenchymal Stromal Cells (MSCs)-based therapies are rapidly gaining interest in veterinary medicine. Cellular therapy represents a new challenge for practitioners and requires precise coordination between the cell processing laboratory and the veterinary clinic. Cryopreservation is the best method to provide fast, in-time, and long-distance delivery of cells for therapeutic applications. However, potentially toxic cryoprotectants and xenobiotic products make the direct administration of cells impracticable for patients. Alternatively, the cells may be resuspended in a ready-to-use vehicle and shipped to the veterinary clinic. In this study, two nutrient-poor vehicles (physiologic saline and ringer lactate solutions) and two nutrient-rich vehicles (the releasate derived from autologous Platelet Poor Plasma and Platelet Rich Plasma) were tested on adipose tissue-derived canine MSCs (AD-MSCs). AD-MSCs stored for 2, 4, or 24 h in the different media were compared regarding mortality, metabolic activity, and replicative capacity. Furthermore, antioxidant activity and the pattern of expression of genes related to AD-MSCs function were performed following 24 h of storage. The results showed that all the different vehicles preserve cell vitality and replication following short-term storage. In long-term storage, the vehicle and cell density affect cell vitality, proliferation, and gene expression (CCL-2, CXCR-4, and TSG-6). Nutrient-rich vehicles seem better suited to preserve cell functionalities in this contest.
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(This article belongs to the Special Issue Selected Papers Associated with 2023 STEMNET MEETING)
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Open AccessArticle
Transcriptome Sequencing Reveals the Mechanism of Auxin Regulation during Root Expansion in Carrot
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Xuan Li, Xuemin Yan, Zhe Wu, Leiping Hou and Meilan Li
Int. J. Mol. Sci. 2024, 25(6), 3425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063425 - 18 Mar 2024
Abstract
Carrot is an important vegetable with roots as the edible organ. A complex regulatory network controls root growth, in which auxin is one of the key players. To clarify the molecular mechanism on auxin regulating carrot root expansion, the growth process and the
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Carrot is an important vegetable with roots as the edible organ. A complex regulatory network controls root growth, in which auxin is one of the key players. To clarify the molecular mechanism on auxin regulating carrot root expansion, the growth process and the indole-3-acetic acid (IAA) content in the roots were measured in this experiment. It was found that the rapid expansion period of the root was from 34 to 41 days after sowing and the IAA content was the highest during this period. The root growth then slowed down and the IAA levels decreased. Using the transcriptome sequencing database, we analyzed the expression of IAA-metabolism-related genes and found that the expression of most of the IAA synthesis genes, catabolism genes, and genes related to signal transduction was consistent with the changes in IAA content during root expansion. Among them, a total of 31 differentially expressed genes (DEGs) were identified, including 10 IAA synthesis genes, 8 degradation genes, and 13 genes related to signal transduction. Analysis of the correlations between the DEGs and IAA levels showed that the following genes were closely related to root development: three synthesis genes, YUCCA10 (DCAR_012429), TAR2 (DCAR_026162), and AMI1 (DCAR_003244); two degradation genes, LPD1 (DCAR_023341) and AACT1 (DCAR_010070); and five genes related to signal transduction, IAA22 (DCAR_012516), IAA13 (DCAR_012591), IAA27 (DCAR_023070), IAA14 (DCAR_027269), and IAA7 (DCAR_030713). These results provide a reference for future studies on the mechanism of root expansion in carrots.
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(This article belongs to the Section Molecular Plant Sciences)
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Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways
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Qiuxia Lin, Binbin Zhang, Manyun Dai, Yan Cheng and Fei Li
Int. J. Mol. Sci. 2024, 25(6), 3424; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063424 - 18 Mar 2024
Abstract
Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice;
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Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression.
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(This article belongs to the Section Biochemistry)
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Nocardia cyriacigeorgica Elicits Gut Disturbances in a Leaky Gut Model of Colitis, but Not the Harmful Cascade Leading to Gut-First Parkinson’s Disease
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João Duarte Magalhães, Emanuel Candeias, Inês Melo-Marques, António E. Abreu, Ana Raquel Pereira-Santos, Ana Raquel Esteves, Sandra Morais Cardoso and Nuno Empadinhas
Int. J. Mol. Sci. 2024, 25(6), 3423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063423 - 18 Mar 2024
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with an unknown cause. Recent research has highlighted the importance of the gut in neuronal and immune maturation through the exchange of nutrients and cellular signals. This has led to the “gut-first PD” hypothesis, which
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder with an unknown cause. Recent research has highlighted the importance of the gut in neuronal and immune maturation through the exchange of nutrients and cellular signals. This has led to the “gut-first PD” hypothesis, which aims to explain many of the sporadic cases and their prodromal intestinal symptoms, such as constipation and intestinal α-synuclein (aSyn) aggregation. The link between mitochondrial dysfunction and aSyn deposition is central to PD pathophysiology, since they can also trigger pro-inflammatory signals associated with aSyn deposition, potentially contributing to the onset of PD. As mitochondria are derived from ancestral alpha-proteobacteria, other bacteria may specifically target this organelle. We sought to use Nocardia cyriacigeorgica, a bacterium previously associated with parkinsonism, and dextran sulfate sodium (DSS) as pro-inflammatory modulators to gain further insight into the onset of PD. This study indicates that aSyn aggregation plus mitochondrial dysfunction without intestinal barrier leakage are not sufficient to trigger gut-first PD.
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(This article belongs to the Special Issue Mitochondrial Footprint in Neurological Pathology)
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Open AccessCorrection
Correction: Cserző et al. The First Quarter Century of the Dense Alignment Surface Transmembrane Prediction Method. Int. J. Mol. Sci. 2023, 24, 14016
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Miklós Cserző, Birgit Eisenhaber, Frank Eisenhaber, Csaba Magyar and István Simon
Int. J. Mol. Sci. 2024, 25(6), 3422; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063422 - 18 Mar 2024
Abstract
There was an error in the original publication [...]
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(This article belongs to the Special Issue Frontiers in Protein Structure Research)
Open AccessArticle
Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders
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Martina Grandi, Chiara Galber, Cristina Gatto, Veronica Nobile, Cecilia Pucci, Ida Schaldemose Nielsen, Francesco Boldrin, Giovanni Neri, Pietro Chiurazzi, Giancarlo Solaini, Alessandra Baracca, Valentina Giorgio and Elisabetta Tabolacci
Int. J. Mol. Sci. 2024, 25(6), 3421; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063421 - 18 Mar 2024
Abstract
Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the FMR1 gene encoding
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Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the FMR1 gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56–200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.
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(This article belongs to the Special Issue Research on Mitochondria and Cell Death in Disease Diagnosis and Treatment)
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MaSMG7-Mediated Degradation of MaERF12 Facilitates Fusarium oxysporum f. sp. cubense Tropical Race 4 Infection in Musa acuminata
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Huoqing Huang, Siwen Liu, Yile Huo, Yuzhen Tian, Yushan Liu, Ganjun Yi and Chunyu Li
Int. J. Mol. Sci. 2024, 25(6), 3420; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063420 - 18 Mar 2024
Abstract
Modern plant breeding relies heavily on the deployment of susceptibility and resistance genes to defend crops against diseases. The expression of these genes is usually regulated by transcription factors including members of the AP2/ERF family. While these factors are a vital component of
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Modern plant breeding relies heavily on the deployment of susceptibility and resistance genes to defend crops against diseases. The expression of these genes is usually regulated by transcription factors including members of the AP2/ERF family. While these factors are a vital component of the plant immune response, little is known of their specific roles in defense against Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) in banana plants. In this study, we discovered that MaERF12, a pathogen-induced ERF in bananas, acts as a resistance gene against Foc TR4. The yeast two-hybrid assays and protein-protein docking analyses verified the interaction between this gene and MaSMG7, which plays a role in nonsense-mediated RNA decay. The transient expression of MaERF12 in Nicotiana benthamiana was found to induce strong cell death, which could be inhibited by MaSMG7 during co-expression. Furthermore, the immunoblot analyses have revealed the potential degradation of MaERF12 by MaSMG7 through the 26S proteasome pathway. These findings demonstrate that MaSMG7 acts as a susceptibility factor and interferes with MaERF12 to facilitate Foc TR4 infection in banana plants. Our study provides novel insights into the biological functions of the MaERF12 as a resistance gene and MaSMG7 as a susceptibility gene in banana plants. Furthermore, the first discovery of interactions between MaERF12 and MaSMG7 could facilitate future research on disease resistance or susceptibility genes for the genetic improvement of bananas.
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(This article belongs to the Special Issue Molecular Trends and Prospects in Plant-Pathogen Interactions)
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Landscape of FLT3 Variations Associated with Structural and Functional Impact on Acute Myeloid Leukemia: A Computational Study
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Zeenat Mirza, Dalal A. Al-Saedi, Nofe Alganmi and Sajjad Karim
Int. J. Mol. Sci. 2024, 25(6), 3419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063419 - 18 Mar 2024
Abstract
Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this
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Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein’s structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3. Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.
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(This article belongs to the Special Issue Bioinformatics Study in Human Diseases: Integration of Omics Data for Personalized Medicine)
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Autumn Olive (Elaeagnus umbellata Thunb.) Berries Improve Lipid Metabolism and Delay Aging in Middle-Aged Caenorhabditis elegans
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Yebin Kim, Seonghyeon Nam, Jongbin Lim and Miran Jang
Int. J. Mol. Sci. 2024, 25(6), 3418; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063418 (registering DOI) - 18 Mar 2024
Abstract
This study evaluated the positive effects of autumn olive berries (AOBs) extract on delaying aging by improving lipid metabolism in middle-aged Caenorhabditis elegans that had become obese due to a high-glucose (GLU) diet. The total phenolic content and DPPH radical scavenging abilities of
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This study evaluated the positive effects of autumn olive berries (AOBs) extract on delaying aging by improving lipid metabolism in middle-aged Caenorhabditis elegans that had become obese due to a high-glucose (GLU) diet. The total phenolic content and DPPH radical scavenging abilities of freeze-dried AOBs (FAOBs) or spray-dried AOBs (SAOBs) were examined, and FAOBs exhibited better antioxidant activity. HPLC analysis confirmed that catechin is the main phenolic compound of AOBs; its content was 5.95 times higher in FAOBs than in SAOBs. Therefore, FAOBs were used in subsequent in vivo experiments. FAOBs inhibited lipid accumulation in both the young adult and middle-aged groups in a concentration-dependent manner under both normal and 2% GLU conditions. Additionally, FAOBs inhibited ROS accumulation in a concentration-dependent manner under normal and 2% GLU conditions in the middle-aged worms. In particular, FAOB also increased body bending and egg production in middle-aged worms. To confirm the intervention of genetic factors related to lipid metabolism from the effects of FAOB, body lipid accumulation was confirmed using worms deficient in the daf-16, atgl-1, aak-1, and akt-1 genes. Regarding the effect of FAOB on reducing lipid accumulation, the impact was nullified in daf-16-deficient worms under the 2% GLU condition, and nullified in both the daf-16- and atgl-1-deficient worms under fasting conditions. In conclusion, FAOB mediated daf-16 and atgl-1 to regulate lipogenesis and lipolysis in middle-aged worms. Our findings suggest that FAOB improves lipid metabolism in metabolically impaired middle-aged worms, contributing to its age-delaying effect.
Full article
(This article belongs to the Special Issue Medicinal Plants and Natural Compounds in Health and Disease: Progresses, Challenges, Opportunities)
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In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells
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Lauria Claeys, Lidiia Zhytnik, Laura Ventura, Lisanne E. Wisse, Elisabeth M. W. Eekhoff, Gerard Pals, Nathalie Bravenboer, Vivi M. Heine and Dimitra Micha
Int. J. Mol. Sci. 2024, 25(6), 3417; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063417 - 18 Mar 2024
Abstract
(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC)
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(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.
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(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)
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Open AccessArticle
Standard Doses of Cholecalciferol Reduce Glucose and Increase Glutamine in Obesity-Related Hypertension: Results of a Randomized Trial
by
Catarina Santos, Rui Carvalho, Ana Mafalda Fonseca, Miguel Castelo Branco, Marco Alves and Ivana Jarak
Int. J. Mol. Sci. 2024, 25(6), 3416; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063416 - 18 Mar 2024
Abstract
In arterial hypertension, the dysregulation of several metabolic pathways is closely associated with chronic immune imbalance and inflammation progression. With time, these disturbances lead to the development of progressive disease and end-organ involvement. However, the influence of cholecalciferol on metabolic pathways as a
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In arterial hypertension, the dysregulation of several metabolic pathways is closely associated with chronic immune imbalance and inflammation progression. With time, these disturbances lead to the development of progressive disease and end-organ involvement. However, the influence of cholecalciferol on metabolic pathways as a possible mechanism of its immunomodulatory activity in obesity-related hypertension is not known. In a phase 2, randomized, single-center, 24-week trial, we evaluated, as a secondary outcome, the serum metabolome of 36 age- and gender-matched adults with obesity-related hypertension and vitamin D deficiency, before and after supplementation with cholecalciferol therapy along with routine medication. The defined endpoint was the assessment of circulating metabolites using a nuclear magnetic resonance-based metabolomics approach. Univariate and multivariate analyses were used to evaluate the systemic metabolic alterations caused by cholecalciferol. In comparison with normotensive controls, hypertensive patients presented overall decreased expression of several amino acids (p < 0.05), including amino acids with ketogenic and glucogenic properties as well as aromatic amino acids. Following cholecalciferol supplementation, increases were observed in glutamine (p < 0.001) and histidine levels (p < 0.05), with several other amino acids remaining unaffected. Glucose (p < 0.05) and acetate (p < 0.05) decreased after 24 weeks in the group taking the supplement, and changes in the saturation of fatty acids (p < 0.05) were also observed, suggesting a role of liposoluble vitamin D in lipid metabolism. Long-term cholecalciferol supplementation in chronically obese and overweight hypertensives induced changes in the blood serum metabolome, which reflected systemic metabolism and may have fostered a new microenvironment for cell proliferation and biology. Of note, the increased availability of glutamine may be relevant for the proliferation of different T-cell subsets.
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(This article belongs to the Special Issue Recent Molecular Developments in Obesity)
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Hsp70 and Calcitonin Receptor Protein in Extracellular Vesicles from Glioblastoma Multiforme: Biomarkers with Putative Roles in Carcinogenesis and Potential for Differentiating Tumor Types
by
Giusi Alberti, Christian M. Sánchez-López, Antonio Marcilla, Rosario Barone, Celeste Caruso Bavisotto, Francesca Graziano, Everly Conway de Macario, Alberto J. L. Macario, Fabio Bucchieri, Francesco Cappello, Claudia Campanella and Francesca Rappa
Int. J. Mol. Sci. 2024, 25(6), 3415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063415 - 18 Mar 2024
Abstract
Glioblastoma multiforme (GBM) is a malignancy of bad prognosis, and advances in early detection and treatment are needed. GBM is heterogenous, with varieties differing in malignancy within a tumor of a patient and between patients. Means are needed to distinguish these GMB forms,
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Glioblastoma multiforme (GBM) is a malignancy of bad prognosis, and advances in early detection and treatment are needed. GBM is heterogenous, with varieties differing in malignancy within a tumor of a patient and between patients. Means are needed to distinguish these GMB forms, so that specific strategies can be deployed for patient management. We study the participation of the chaperone system (CS) in carcinogenesis. The CS is dynamic, with its members moving around the body in extracellular vesicles (EVs) and interacting with components of other physiological systems in health and disease, including GBM. Here, we describe the finding of high amounts of Hsp70 (HSPA1A) and the calcitonin receptor protein (CTR) in EVs in patients with GBM. We present a standardized protocol for collecting, purifying, and characterizing EVs carrying Hsp70 and CTR in plasma-derived EVs from patients with GBM. EVs from GBM patients were obtained just before tumor ablative surgery (T0) and 7 days afterwards (T1); Hsp70 was highly elevated at T0 and less so at T1, and CTR was greatly increased at T0 and reduced to below normal values at T1. Our results encourage further research to assess Hsp70 and CTR as biomarkers for differentiating tumor forms and to determine their roles in GBM carcinogenesis.
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(This article belongs to the Special Issue Extracellular Vesicles and Nanoparticles)
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Open AccessReview
New Strategies for Macrophage Re-Education in Cancer: An Update
by
Nadia Lampiasi
Int. J. Mol. Sci. 2024, 25(6), 3414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063414 - 18 Mar 2024
Abstract
The association between cancer and inflammation is well established. Chronic inflammation represents a fundamental step in the development and progression of some types of cancer. Tumors are composed of a heterogeneous population of infiltrating cells including macrophages, fibroblasts, lymphocytes, granulocytes, and mast cells,
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The association between cancer and inflammation is well established. Chronic inflammation represents a fundamental step in the development and progression of some types of cancer. Tumors are composed of a heterogeneous population of infiltrating cells including macrophages, fibroblasts, lymphocytes, granulocytes, and mast cells, which respond to signals from the microenvironment and, in turn, produce cytokines, chemokines, transcription factors, receptors, and miRNAs. Recent data demonstrate that, in addition to classical (M1) and alternative (M2) macrophage subtypes, there are many intermediate subtypes that potentially play different roles in response to environmental stimuli. Tumors are infiltrated by macrophages called TAMs that mainly display an M2-like phenotype and tumor growth-permissive activities. There is a bidirectional interaction between tumor cells and tumor-infiltrating cells that determines macrophage polarization and ultimately tumor progression or regression. These complex interactions are still unclear but understanding them is fundamental for the development of new therapeutic strategies. Re-educating tumor-permissive macrophages into anti-tumor macrophages is a new focus of research. This review aims to analyze the most recent articles investigating the interplay between tumors, tumor-infiltrating cells, and TAMs, and the strategies for re-educating tumor-permissive macrophages.
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(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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Snail Transcriptionally Represses Brachyury to Promote the Mesenchymal-Epithelial Transition in Ascidian Notochord Cells
by
Bingtong Wu, Xiuke Ouyang, Xiuxia Yang and Bo Dong
Int. J. Mol. Sci. 2024, 25(6), 3413; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063413 - 18 Mar 2024
Abstract
Mesenchymal-epithelial transition (MET) is a widely spread and evolutionarily conserved process across species during development. In Ciona embryogenesis, the notochord cells undergo the transition from the non-polarized mesenchymal state into the polarized endothelial-like state to initiate the lumen formation between adjacent cells. Based
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Mesenchymal-epithelial transition (MET) is a widely spread and evolutionarily conserved process across species during development. In Ciona embryogenesis, the notochord cells undergo the transition from the non-polarized mesenchymal state into the polarized endothelial-like state to initiate the lumen formation between adjacent cells. Based on previously screened MET-related transcription factors by ATAC-seq and Smart-Seq of notochord cells, Ciona robusta Snail (Ci-Snail) was selected for its high-level expression during this period. Our current knockout results demonstrated that Ci-Snail was required for notochord cell MET. Importantly, overexpression of the transcription factor Brachyury in notochord cells resulted in a similar phenotype with failure of lumen formation and MET. More interestingly, expression of Ci-Snail in the notochord cells at the late tailbud stage could partially rescue the MET defect caused by Brachyury-overexpression. These results indicated an inverse relationship between Ci-Snail and Brachyury during notochord cell MET, which was verified by RT-qPCR analysis. Moreover, the overexpression of Ci-Snail could significantly inhibit the transcription of Brachyury, and the CUT&Tag-qPCR analysis demonstrated that Ci-Snail is directly bound to the upstream region of Brachyury. In summary, we revealed that Ci-Snail promoted the notochord cell MET and was essential for lumen formation via transcriptionally repressing Brachyury.
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(This article belongs to the Section Molecular Biology)
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Perineuronal Nets in the CNS: Architects of Memory and Potential Therapeutic Target in Neuropsychiatric Disorders
by
Xue Li, Xianwen Wu, Tangsheng Lu, Chenyan Kuang, Yue Si, Wei Zheng, Zhonghao Li and Yanxue Xue
Int. J. Mol. Sci. 2024, 25(6), 3412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063412 - 18 Mar 2024
Abstract
The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along
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The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.
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(This article belongs to the Section Molecular Neurobiology)
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