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
De Novo Assembly and Comparative Analysis of Mitochondrial Genomes of Two Pueraria montana Varieties
Int. J. Mol. Sci. 2024, 25(11), 5656; https://doi.org/10.3390/ijms25115656 (registering DOI) - 22 May 2024
Abstract
Pueraria montana is a species with important medicinal value and a complex genetic background. In this study, we sequenced and assembled the mitochondrial (mt) genomes of two varieties of P. montana. The mt genome lengths of P. montana var. thomsonii and P.
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Pueraria montana is a species with important medicinal value and a complex genetic background. In this study, we sequenced and assembled the mitochondrial (mt) genomes of two varieties of P. montana. The mt genome lengths of P. montana var. thomsonii and P. montana var. montana were 457,390 bp and 456,731 bp, respectively. Both P. montana mitogenomes showed a multi-branched structure consisting of two circular molecules, with 56 genes annotated, comprising 33 protein-coding genes, 18 tRNA genes (trnC-GCA and trnM-CAU are multi-copy genes), and 3 rRNA genes. Then, 207 pairs of long repeats and 96 simple sequence repeats (SSRs) were detected in the mt genomes of P. montana, and 484 potential RNA-editing sites were found across the 33 mitochondrial protein-coding genes of each variety. Additionally, a syntenic sequence analysis showed a high collinearity between the two mt genomes. This work is the first to analyze the mt genomes of P. montana. It can provide information that can be used to analyze the structure of mt genomes of higher plants and provide a foundation for future comparative genomic studies and evolutionary biology research in related species.
Full article
(This article belongs to the Section Molecular Genetics and Genomics)
Open AccessArticle
The Influence of Mesotrione on Human Colorectal Adenocarcinoma Cells and Possibility of Its Toxicity Mitigation by Cichoric Acid
by
Agata Jabłońska-Trypuć, Urszula Wydro, Elżbieta Wołejko, Monika Kalinowska, Grzegorz Świderski, Rafał Krętowski, Monika Naumowicz, Paweł Kondzior, Marzanna Cechowska-Pasko and Włodzimierz Lewandowski
Int. J. Mol. Sci. 2024, 25(11), 5655; https://doi.org/10.3390/ijms25115655 - 22 May 2024
Abstract
Mesotrione, as a widely used herbicide, is present in the environment in detectable amounts, causing serious damage. Here, we aimed to investigate the effect of mesotrione on Caco-2 cells and the possibility of its toxicity mitigation by cichoric acid. Therefore, we analyzed the
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Mesotrione, as a widely used herbicide, is present in the environment in detectable amounts, causing serious damage. Here, we aimed to investigate the effect of mesotrione on Caco-2 cells and the possibility of its toxicity mitigation by cichoric acid. Therefore, we analyzed the cytotoxicity of both these compounds and the selected oxidative stress parameters, apoptosis and interaction of both the tested compounds with the cell membrane and their accumulation within the cells. In cytotoxicity studies, the stimulating activity of mesotrione was observed, and simultaneously, the inhibitory effect of cichoric acid was noticed. This effect was related to the results of oxidative stress analysis and apoptosis measurements. The activity level of key enzymes (glutathione peroxidase, catalase and superoxide dismutase) in Caco-2 cells exposed to cichoric acid was higher as compared to that of the control. The treatment with mesotrione did not induce apoptosis in the Caco-2 cells. The penetration of the studied compounds into the Caco-2 cells was measured by using an HPLC methodology, and the results indicate mesotrione’s high penetration capacity. The distribution of charge on the surface of the cell membranes changed under the influence of both compounds. Considering the mutual interactions of beneficial and potentially toxic food ingredients, it should be noted that, despite the observed favorable trend, cichoric acid is not able to overcome the toxic and cancer-stimulating effects of this pesticide.
Full article
(This article belongs to the Special Issue Toxicity Mechanism of Emerging Pollutants)
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Open AccessArticle
A Causal Regulation Modeling Algorithm for Temporal Events with Application to Escherichia coli’s Aerobic to Anaerobic Transition
by
Yigang Chen, Runbo Mao, Jiatong Xu, Yixian Huang, Jingyi Xu, Shidong Cui, Zihao Zhu, Xiang Ji, Shenghan Huang, Yanzhe Huang, Hsi-Yuan Huang, Shih-Chung Yen, Yang-Chi-Duang Lin and Hsien-Da Huang
Int. J. Mol. Sci. 2024, 25(11), 5654; https://doi.org/10.3390/ijms25115654 - 22 May 2024
Abstract
Time-series experiments are crucial for understanding the transient and dynamic nature of biological phenomena. These experiments, leveraging advanced classification and clustering algorithms, allow for a deep dive into the cellular processes. However, while these approaches effectively identify patterns and trends within data, they
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Time-series experiments are crucial for understanding the transient and dynamic nature of biological phenomena. These experiments, leveraging advanced classification and clustering algorithms, allow for a deep dive into the cellular processes. However, while these approaches effectively identify patterns and trends within data, they often need to improve in elucidating the causal mechanisms behind these changes. Building on this foundation, our study introduces a novel algorithm for temporal causal signaling modeling, integrating established knowledge networks with sequential gene expression data to elucidate signal transduction pathways over time. Focusing on Escherichia coli’s (E. coli) aerobic to anaerobic transition (AAT), this research marks a significant leap in understanding the organism’s metabolic shifts. By applying our algorithm to a comprehensive E. coli regulatory network and a time-series microarray dataset, we constructed the cross-time point core signaling and regulatory processes of E. coli’s AAT. Through gene expression analysis, we validated the primary regulatory interactions governing this process. We identified a novel regulatory scheme wherein environmentally responsive genes, soxR and oxyR, activate fur, modulating the nitrogen metabolism regulators fnr and nac. This regulatory cascade controls the stress regulators ompR and lrhA, ultimately affecting the cell motility gene flhD, unveiling a novel regulatory axis that elucidates the complex regulatory dynamics during the AAT process. Our approach, merging empirical data with prior knowledge, represents a significant advance in modeling cellular signaling processes, offering a deeper understanding of microbial physiology and its applications in biotechnology.
Full article
(This article belongs to the Special Issue Complex Networks, Bio-Molecular Systems, and Machine Learning 2.0)
Open AccessArticle
In Vitro Screening of Ecotoxic and Cytotoxic Activities of Ailanthus altissima Leaf Extract against Target and Non-Target Plant and Animal Cells
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Maria Denisa Cocîrlea, Natalia Simionescu, Anca Roxana Petrovici, Mihaela Silion, Barbara Biondi, Luana Lastella and Simona Oancea
Int. J. Mol. Sci. 2024, 25(11), 5653; https://doi.org/10.3390/ijms25115653 - 22 May 2024
Abstract
Ailanthus altissima, an invasive plant species, exhibits pharmacological properties, but also some allergic effects on humans. This study aimed to evaluate the potential toxicity of A. altissima leaves, using a complex approach towards different organisms. The ecotoxic impact of a crude extract
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Ailanthus altissima, an invasive plant species, exhibits pharmacological properties, but also some allergic effects on humans. This study aimed to evaluate the potential toxicity of A. altissima leaves, using a complex approach towards different organisms. The ecotoxic impact of a crude extract was investigated on seeds germination and brine shrimp lethality. Cytotoxicity was studied in vitro using non-target (haemolysis, liposomal model, fibroblast), and target (cancer cells) assays. Leaf extract at 1000 µg/mL significantly inhibited wheat and tomato germination, while no significant effects were found on parsley germination. A slight stimulatory effect on wheat and tomato germination was found at 125 µg/mL. In a brine shrimp-test, the extract showed a low toxicity at 24 h post-exposure (LC50 = 951.04 ± 28.26 μg/mL), the toxic effects increasing with the exposure time and extract concentration. Leaf extract caused low hematotoxicity. The extract was biocompatible with human gingival fibroblasts. No anti-proliferative effect was found within the concentration range of 10–500 µg/mL on malignant melanoma (MeWo) and hepatocellular carcinoma (HepG2). In a liposomal model-test, the extract proved to possess low capability to alter the eukaryotic cell-mimicking membranes within the tested concentration range. Given the low to moderate toxicity on tested organisms/cells, the A. altissima autumn leaves may find useful applications.
Full article
(This article belongs to the Special Issue Investigation of Natural Products as Sources of Bioactive Molecules)
Open AccessReview
Deciphering the Complex Immunopathogenesis of Alopecia Areata
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Ingrid Šutić Udović, Nika Hlača, Larisa Prpić Massari, Ines Brajac, Marija Kaštelan and Marijana Vičić
Int. J. Mol. Sci. 2024, 25(11), 5652; https://doi.org/10.3390/ijms25115652 - 22 May 2024
Abstract
Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and
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Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient’s quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.
Full article
(This article belongs to the Section Molecular Immunology)
Open AccessArticle
Structural and Interactional Analysis of the Flavonoid Pathway Proteins: Chalcone Synthase, Chalcone Isomerase and Chalcone Isomerase-like Protein
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Jacob A. Lewis, Eric P. Jacobo, Nathan Palmer, Wilfred Vermerris, Scott E. Sattler, James A Brozik, Gautam Sarath and ChulHee Kang
Int. J. Mol. Sci. 2024, 25(11), 5651; https://doi.org/10.3390/ijms25115651 - 22 May 2024
Abstract
Chalcone synthase (CHS) and chalcone isomerase (CHI) catalyze the first two committed steps of the flavonoid pathway that plays a pivotal role in the growth and reproduction of land plants, including UV protection, pigmentation, symbiotic nitrogen fixation, and pathogen resistance. Based on the
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Chalcone synthase (CHS) and chalcone isomerase (CHI) catalyze the first two committed steps of the flavonoid pathway that plays a pivotal role in the growth and reproduction of land plants, including UV protection, pigmentation, symbiotic nitrogen fixation, and pathogen resistance. Based on the obtained X-ray crystal structures of CHS, CHI, and chalcone isomerase-like protein (CHIL) from the same monocotyledon, Panicum virgatum, along with the results of the steady-state kinetics, spectroscopic/thermodynamic analyses, intermolecular interactions, and their effect on each catalytic step are proposed. In addition, PvCHI’s unique activity for both naringenin chalcone and isoliquiritigenin was analyzed, and the observed hierarchical activity for those type-I and -II substrates was explained with the intrinsic characteristics of the enzyme and two substrates. The structure of PvCHS complexed with naringenin supports uncompetitive inhibition. PvCHS displays intrinsic catalytic promiscuity, evident from the formation of p-coumaroyltriacetic acid lactone (CTAL) in addition to naringenin chalcone. In the presence of PvCHIL, conversion of p-coumaroyl-CoA to naringenin through PvCHS and PvCHI displayed ~400-fold increased Vmax with reduced formation of CTAL by 70%. Supporting this model, molecular docking, ITC (Isothermal Titration Calorimetry), and FRET (Fluorescence Resonance Energy Transfer) indicated that both PvCHI and PvCHIL interact with PvCHS in a non-competitive manner, indicating the plausible allosteric effect of naringenin on CHS. Significantly, the presence of naringenin increased the affinity between PvCHS and PvCHIL, whereas naringenin chalcone decreased the affinity, indicating a plausible feedback mechanism to minimize spontaneous incorrect stereoisomers. These are the first findings from a three-body system from the same species, indicating the importance of the macromolecular assembly of CHS-CHI-CHIL in determining the amount and type of flavonoids produced in plant cells.
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(This article belongs to the Section Biochemistry)
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Open AccessArticle
Neurotoxicity and Developmental Neurotoxicity of Copper Sulfide Nanoparticles on a Human Neuronal In-Vitro Test System
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Michael Stern, Nandipha Botha, Karen J. Cloete, Malik Maaza, Saime Tan and Gerd Bicker
Int. J. Mol. Sci. 2024, 25(11), 5650; https://doi.org/10.3390/ijms25115650 - 22 May 2024
Abstract
Nanoparticles (NPs) are becoming increasingly important novel materials for many purposes, including basic research, medicine, agriculture, and engineering. Increasing human and environmental exposure to these promising compounds requires assessment of their potential health risks. While the general direct cytotoxicity of NPs is often
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Nanoparticles (NPs) are becoming increasingly important novel materials for many purposes, including basic research, medicine, agriculture, and engineering. Increasing human and environmental exposure to these promising compounds requires assessment of their potential health risks. While the general direct cytotoxicity of NPs is often routinely measured, more indirect possible long-term effects, such as reproductive or developmental neurotoxicity (DNT), have been studied only occasionally and, if so, mostly on non-human animal models, such as zebrafish embryos. In this present study, we employed a well-characterized human neuronal precursor cell line to test the concentration-dependent DNT of green-manufactured copper sulfide (CuS) nanoparticles on crucial early events in human brain development. CuS NPs turned out to be generally cytotoxic in the low ppm range. Using an established prediction model, we found a clear DNT potential of CuS NPs on neuronal precursor cell migration and neurite outgrowth, with IC50 values 10 times and 5 times, respectively, lower for the specific DNT endpoint than for general cytotoxicity. We conclude that, in addition to the opportunities of NPs, their risks to human health should be carefully considered.
Full article
(This article belongs to the Special Issue Advances in Developmental Neurotoxicology)
Open AccessArticle
The Significant Role of PA28αβ in CD8+ T Cell-Mediated Graft Rejection Contrasts with Its Negligible Impact on the Generation of MHC-I Ligands
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Katharina Inholz, Ulrika Bader, Sarah Mundt and Michael Basler
Int. J. Mol. Sci. 2024, 25(11), 5649; https://doi.org/10.3390/ijms25115649 - 22 May 2024
Abstract
The proteasome generates the majority of peptides presented on MHC class I molecules. The cleavage pattern of the proteasome has been shown to be changed via the proteasome activator (PA)28 alpha beta (PA28αβ). In particular, several immunogenic peptides have been reported to be
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The proteasome generates the majority of peptides presented on MHC class I molecules. The cleavage pattern of the proteasome has been shown to be changed via the proteasome activator (PA)28 alpha beta (PA28αβ). In particular, several immunogenic peptides have been reported to be PA28αβ-dependent. In contrast, we did not observe a major impact of PA28αβ on the generation of different major histocompatibility complex (MHC) classI ligands. PA28αβ-knockout mice infected with the lymphocytic choriomeningitis virus (LCMV) or vaccinia virus showed a normal cluster of differentiation (CD) 8 response and viral clearance. However, we observed that the adoptive transfer of wild-type cells into PA28αβ-knockout mice led to graft rejection, but not vice versa. Depletion experiments showed that the observed rejection was mediated by CD8+ cytotoxic T cells. These data indicate that PA28αβ might be involved in the development of the CD8+ T cell repertoire in the thymus. Taken together, our data suggest that PA28αβ is a crucial factor determining T cell selection and, therefore, impacts graft acceptance.
Full article
(This article belongs to the Collection Feature Papers in “Molecular Biology”)
Open AccessArticle
Novel Proteins of the High-Affinity Nitrate Transporter Family NRT2, SaNRT2.1 and SaNRT2.5, from the Euhalophyte Suaeda altissima: Molecular Cloning and Expression Analysis
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Dmitrii E. Khramov, Elena I. Rostovtseva, Dmitrii A. Matalin, Alena O. Konoshenkova, Olga I. Nedelyaeva, Vadim S. Volkov, Yurii V. Balnokin and Larissa G. Popova
Int. J. Mol. Sci. 2024, 25(11), 5648; https://doi.org/10.3390/ijms25115648 - 22 May 2024
Abstract
Two genes of nitrate transporters SaNRT2.1 and SaNRT2.5, putative orthologs of high-affinity nitrate transporter genes AtNRT2.1 and AtNRT2.5 from Arabidopsis thaliana, were cloned from the euhalophyte Suaeda altissima. Phylogenetic bioinformatic analysis demonstrated that the proteins SaNRT2.1 and SaNRT2.5 exhibited higher
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Two genes of nitrate transporters SaNRT2.1 and SaNRT2.5, putative orthologs of high-affinity nitrate transporter genes AtNRT2.1 and AtNRT2.5 from Arabidopsis thaliana, were cloned from the euhalophyte Suaeda altissima. Phylogenetic bioinformatic analysis demonstrated that the proteins SaNRT2.1 and SaNRT2.5 exhibited higher levels of homology to the corresponding proteins from the plants of family Amaranthaceae; the similarity of amino acid sequences between proteins SaNRT2.1 and SaNRT2.5 was lower (54%). Both SaNRT2.1 and SaNRT2.5 are integral membrane proteins forming 12 transmembrane helices as predicted by topological modeling. An attempt to demonstrate nitrate transporting activity of SaNRT2.1 or SaNRT2.5 by heterologous expression of the genes in the yeast Hansenula (Ogataea) polymorpha mutant strain Δynt1 lacking the only yeast nitrate transporter was not successful. The expression patterns of SaNRT2.1 and SaNRT2.5 were studied in S. altissima plants that were grown in hydroponics under either low (0.5 mM) or high (15 mM) nitrate and salinity from 0 to 750 mM NaCl. The growth of the plants was strongly inhibited by low nitrogen supply while stimulated by NaCl; it peaked at 250 mM NaCl for high nitrate and at 500 mM NaCl for low nitrate. Under low nitrate supply, nitrate contents in S. altissima roots, leaves and stems were reduced but increased in leaves and stems as salinity in the medium increased. Potassium contents remained stable under salinity treatment from 250 to 750 mM NaCl. Quantitative real-time PCR demonstrated that without salinity, SaNRT2.1 was expressed in all organs, its expression was not influenced by nitrate supply, while SaNRT2.5 was expressed exclusively in roots—its expression rose about 10-fold under low nitrate. Salinity increased expression of both SaNRT2.1 and SaNRT2.5 under low nitrate. SaNRT2.1 peaked in roots at 500 mM NaCl with 15-fold increase; SaNRT2.5 peaked in roots at 500 mM NaCl with 150-fold increase. It is suggested that SaNRT2.5 ensures effective nitrate uptake by roots and functions as an essential high-affinity nitrate transporter to support growth of adult S. altissima plants under nitrogen deficiency.
Full article
(This article belongs to the Special Issue Molecular Mechanisms of Plant Abiotic Stress Tolerance)
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Open AccessArticle
Systems Genome: Coordinated Gene Activity Networks, Recurring Coordination Modules, and Genome Homeostasis in Developing Neurons
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Siddhartha Dhiman, Namya Manoj, Michal Liput, Amit Sangwan, Justin Diehl, Anna Balcerak, Sneha Sudhakar, Justyna Augustyniak, Josep M. Jornet, Yongho Bae, Ewa K. Stachowiak, Anirban Dutta and Michal K. Stachowiak
Int. J. Mol. Sci. 2024, 25(11), 5647; https://doi.org/10.3390/ijms25115647 - 22 May 2024
Abstract
Abstract: As human progenitor cells differentiate into neurons, the activities of many genes change; these changes are maintained within a narrow range, referred to as genome homeostasis. This process, which alters the synchronization of the entire expressed genome, is distorted in neurodevelopmental
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Abstract: As human progenitor cells differentiate into neurons, the activities of many genes change; these changes are maintained within a narrow range, referred to as genome homeostasis. This process, which alters the synchronization of the entire expressed genome, is distorted in neurodevelopmental diseases such as schizophrenia. The coordinated gene activity networks formed by altering sets of genes comprise recurring coordination modules, governed by the entropy-controlling action of nuclear FGFR1, known to be associated with DNA topology. These modules can be modeled as energy-transferring circuits, revealing that genome homeostasis is maintained by reducing oscillations (noise) in gene activity while allowing gene activity changes to be transmitted across networks; this occurs more readily in neuronal committed cells than in neural progenitors. These findings advance a model of an “entangled” global genome acting as a flexible, coordinated homeostatic system that responds to developmental signals, is governed by nuclear FGFR1, and is reprogrammed in disease.
Full article
(This article belongs to the Special Issue Advances in Stem Cells and Organoid Development: Exploring Molecular, Metabolic and Electro-Synaptic Mechanisms Using Systems Approach)
Open AccessReview
Cross-Species Insights into Autosomal Dominant Polycystic Kidney Disease: Provide an Alternative View on Research Advancement
by
Jianing Luo, Yuan Zhang, Sakthidasan Jayaprakash, Lenan Zhuang and Jin He
Int. J. Mol. Sci. 2024, 25(11), 5646; https://doi.org/10.3390/ijms25115646 - 22 May 2024
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal
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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal kidney tissue, often accompanied by interstitial fibrosis and inflammation, and significantly impair renal function, leading to end-stage renal disease. Currently, the precise mechanisms underlying ADPKD remain elusive, and a definitive cure has yet to be discovered. This review delineates the epidemiology, pathological features, and clinical diagnostics of ADPKD or ADPKD-like disease across human populations, as well as companion animals and other domesticated species. A light has been shed on pivotal genes and biological pathways essential for preventing and managing ADPKD, which underscores the importance of cross-species research in addressing this complex condition. Treatment options are currently limited to Tolvaptan, dialysis, or surgical excision of large cysts. However, comparative studies of ADPKD across different species hold promise for unveiling novel insights and therapeutic strategies to combat this disease.
Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle
Development of a Sampling and Storage Protocol of Extracellular Vesicles (EVs)—Establishment of the First EV Biobank for Polytraumatized Patients
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Birte Weber, Aileen Ritter, Jiaoyan Han, Inna Schaible, Ramona Sturm, Borna Relja, Markus Huber-Lang, Frank Hildebrand, Christiane Pallas, Marek Widera, Dirk Henrich, Ingo Marzi and Liudmila Leppik
Int. J. Mol. Sci. 2024, 25(11), 5645; https://doi.org/10.3390/ijms25115645 - 22 May 2024
Abstract
In the last few years, several studies have emphasized the existence of injury-specific EV “barcodes” that could have significant importance for the precise diagnosis of different organ injuries in polytrauma patients. To expand the research potential of the NTF (network trauma research) biobank
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In the last few years, several studies have emphasized the existence of injury-specific EV “barcodes” that could have significant importance for the precise diagnosis of different organ injuries in polytrauma patients. To expand the research potential of the NTF (network trauma research) biobank of polytraumatized patients, the NTF research group decided to further establish a biobank for EVs. However, until now, the protocols for the isolation, characterization, and storage of EVs for biobank purposes have not been conceptualized. Plasma and serum samples from healthy volunteers (n = 10) were used. Three EV isolation methods of high relevance for the work with patients’ samples (ultracentrifugation, size exclusion chromatography, and immune magnetic bead-based isolation) were compared. EVs were quantified using nanoparticle tracking analysis, EV proteins, and miRNAs. The effects of different isolation solutions; the long storage of samples (up to 3 years); and the sensibility of EVs to serial freezing–thawing cycles and different storage conditions (RT, 4/−20/−80 °C, dry ice) were evaluated. The SEC isolation method was considered the most suitable for EV biobanking. We did not find any difference in the quantity of EVs between serum and plasma-EVs. The importance of particle-free PBS as an isolation solution was confirmed. Plasma that has been frozen for a long time can also be used as a source of EVs. Serial freezing–thawing cycles were found to affect the mean size of EVs but not their amount. The storage of EV samples for 5 days on dry ice significantly reduced the EV protein concentration.
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(This article belongs to the Section Molecular Biology)
Open AccessArticle
SCN1A Channels a Wide Range of Epileptic Phenotypes: Report of Novel and Known Variants with Variable Presentations
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Danai Veltra, Virginia Theodorou, Marina Katsalouli, Pelagia Vorgia, Georgios Niotakis, Triantafyllia Tsaprouni, Roser Pons, Konstantina Kosma, Afroditi Kampouraki, Irene Tsoutsou, Periklis Makrythanasis, Kyriaki Kekou, Joanne Traeger-Synodinos and Christalena Sofocleous
Int. J. Mol. Sci. 2024, 25(11), 5644; https://doi.org/10.3390/ijms25115644 - 22 May 2024
Abstract
SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel’s function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation
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SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel’s function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants’ characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions.
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(This article belongs to the Special Issue Molecular Diagnostics and Therapeutics of Epileptic Neurodevelopment)
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Open AccessArticle
Adar Regulates Drosophila melanogaster Spermatogenesis via Modulation of BMP Signaling
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Qian Zhang, Xinxin Fan, Fang Fu, Yuedan Zhu, Guanzheng Luo and Haiyang Chen
Int. J. Mol. Sci. 2024, 25(11), 5643; https://doi.org/10.3390/ijms25115643 - 22 May 2024
Abstract
The dynamic process of Drosophila spermatogenesis involves asymmetric division, mitosis, and meiosis, which ultimately results in the production of mature spermatozoa. Disorders of spermatogenesis can lead to infertility in males. ADAR (adenosine deaminase acting on RNA) mutations in Drosophila cause male infertility, yet
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The dynamic process of Drosophila spermatogenesis involves asymmetric division, mitosis, and meiosis, which ultimately results in the production of mature spermatozoa. Disorders of spermatogenesis can lead to infertility in males. ADAR (adenosine deaminase acting on RNA) mutations in Drosophila cause male infertility, yet the causative factors remain unclear. In this study, immunofluorescence staining was employed to visualize endogenous ADAR proteins and assess protein levels via fluorescence-intensity analysis. In addition, the early differentiation disorders and homeostatic alterations during early spermatogenesis in the testes were examined through quantification of transit-amplifying region length, counting the number of GSCs (germline stem cells), and fertility experiments. Our findings suggest that deletion of ADAR causes testicular tip transit-amplifying cells to accumulate and become infertile in older male Drosophila. By overexpressing ADAR in early germline cells, male infertility can be partially rescued. Transcriptome analysis showed that ADAR maintained early spermatogenesis homeostasis through the bone-morphogenetic-protein (BMP) signaling pathway. Taken together, these findings have the potential to help explore the role of ADAR in early spermatogenesis.
Full article
(This article belongs to the Section Molecular Biology)
Open AccessReview
Dentin Mechanobiology: Bridging the Gap between Architecture and Function
by
Xiangting Fu and Hye Sung Kim
Int. J. Mol. Sci. 2024, 25(11), 5642; https://doi.org/10.3390/ijms25115642 - 22 May 2024
Abstract
It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in
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It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in mechanically supporting tooth function. Its intermediate stiffness and viscoelastic properties, attributed to its mineralized, nanofibrous extracellular matrix, provide flexibility, strength, and rigidity, enabling it to withstand mechanical loading without fracturing. Moreover, dentin’s unique architectural features, such as odontoblast processes within dentinal tubules and spatial compartmentalization between odontoblasts in dentin and sensory neurons in pulp, contribute to a distinctive sensory perception of external stimuli while acting as a defensive barrier for the dentin-pulp complex. Since dentin’s architecture governs its functions in nociception and repair in response to mechanical stimuli, understanding dentin mechanobiology is crucial for developing treatments for pain management in dentin-associated diseases and dentin-pulp regeneration. This review discusses how dentin’s physical features regulate mechano-sensing, focusing on mechano-sensitive ion channels. Additionally, we explore advanced in vitro platforms that mimic dentin’s physical features, providing deeper insights into fundamental mechanobiological phenomena and laying the groundwork for effective mechano-therapeutic strategies for dentinal diseases.
Full article
(This article belongs to the Collection Feature Papers in Materials Science)
Open AccessEditorial
Editorial for the IJMS Special Issue on “Neurodevelopmental Disorders: From Epigenetic Basis to Therapeutic Perspectives”
by
Miriam Zappella, Roberto Sacco and Alessandra Micera
Int. J. Mol. Sci. 2024, 25(11), 5641; https://doi.org/10.3390/ijms25115641 - 22 May 2024
Abstract
In this Special Issue, we focus on the complex mechanisms underlying neurodevelopmental disorders (as delineated in the DSM-5), which are a group of neurological disorders that begin in childhood but significantly impact adult life [...]
Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders: From Epigenetic Basis to Therapeutic Perspectives)
Open AccessReview
Metabolic Dysfunction–Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options
by
Piero Portincasa, Mohamad Khalil, Laura Mahdi, Valeria Perniola, Valeria Idone, Annarita Graziani, Gyorgy Baffy and Agostino Di Ciaula
Int. J. Mol. Sci. 2024, 25(11), 5640; https://doi.org/10.3390/ijms25115640 - 22 May 2024
Abstract
The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and
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The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from “nonalcoholic fatty liver disease” (NAFLD) to “metabolic dysfunction-associated fatty liver disease” (MAFLD) and, finally, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut–liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.
Full article
(This article belongs to the Special Issue Strategies to Fight Metabolic Diseases)
Open AccessArticle
Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes
by
Yasmine Ruel, Fatma Moawad, Jérôme Alsarraf, André Pichette, Jean Legault, Davide Brambilla and Roxane Pouliot
Int. J. Mol. Sci. 2024, 25(11), 5639; https://doi.org/10.3390/ijms25115639 - 22 May 2024
Abstract
Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack
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Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1β, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.
Full article
(This article belongs to the Special Issue Psoriatic Arthritis and Skin Diseases: Pathogenesis and Therapies)
Open AccessArticle
Evaluation of Polyphenols Synthesized in Mature Seeds of Common Bean (Phaseolus vulgaris L.) Advanced Mutant Lines
by
Teodora G. Yaneva, Wieslaw Wiczkowski, Andrey S. Marchev, Dida Iserliyska, Milen I. Georgiev and Nasya B. Tomlekova
Int. J. Mol. Sci. 2024, 25(11), 5638; https://doi.org/10.3390/ijms25115638 - 22 May 2024
Abstract
This study aimed to investigate the availability of flavonoids, anthocyanins, and phenolic acids in mutant bean seeds, focusing on M7 mutant lines, and their corresponding initial and local cultivars. HPLC-DAD-MS/MS and HPLC-MS/MS were used to analyze twenty-eight genotypes of common bean. The
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This study aimed to investigate the availability of flavonoids, anthocyanins, and phenolic acids in mutant bean seeds, focusing on M7 mutant lines, and their corresponding initial and local cultivars. HPLC-DAD-MS/MS and HPLC-MS/MS were used to analyze twenty-eight genotypes of common bean. The obtained results suggest that the mutations resulted in four newly synthesized anthocyanins in the mutant bean seeds, namely, delphinidin 3-O-glucoside, cyanidin 3-O-glucoside, pelargonidin 3-O-glucoside, and petunidin 3-O-glucoside, in 20 accessions with colored seed shapes out of the total of 28. Importantly, the initial cultivar with white seeds, as well as the mutant white seeds, did not contain anthocyanins. The mutant lines were classified into groups based on their colors as novel qualitative characteristics. Five phenolic acids were further quantified: ferulic, p-coumaric, caffeic, sinapic, and traces of chlorogenic acids. Flavonoids were represented by epicatechin, quercetin, and luteolin, and their concentrations in the mutant genotypes were several-fold superior compared to those of the initial cultivar. All mutant lines exhibited higher concentrations of phenolic acids and flavonoids. These findings contribute to the understanding of the genetics and biochemistry of phenolic accumulation and anthocyanin production in common bean seeds, which is relevant to health benefits and might have implications for common bean breeding programs and food security efforts.
Full article
(This article belongs to the Special Issue Selected Papers from the International Conference on Plant Systems Biology)
Open AccessReview
PA200-Mediated Proteasomal Protein Degradation and Regulation of Cellular Senescence
by
Pei Wen, Yan Sun, Tian-Xia Jiang and Xiao-Bo Qiu
Int. J. Mol. Sci. 2024, 25(11), 5637; https://doi.org/10.3390/ijms25115637 - 22 May 2024
Abstract
Cellular senescence is closely related to DNA damage, proteasome inactivity, histone loss, epigenetic alterations, and tumorigenesis. The mammalian proteasome activator PA200 (also referred to as PSME4) or its yeast ortholog Blm10 promotes the acetylation-dependent degradation of the core histones during transcription, DNA repair,
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Cellular senescence is closely related to DNA damage, proteasome inactivity, histone loss, epigenetic alterations, and tumorigenesis. The mammalian proteasome activator PA200 (also referred to as PSME4) or its yeast ortholog Blm10 promotes the acetylation-dependent degradation of the core histones during transcription, DNA repair, and spermatogenesis. According to recent studies, PA200 plays an important role in senescence, probably because of its role in promoting the degradation of the core histones. Loss of PA200 or Blm10 is a major cause of the decrease in proteasome activity during senescence. In this paper, recent research progress on the association of PA200 with cellular senescence is summarized, and the potential of PA200 to serve as a therapeutic target in age-related diseases is discussed.
Full article
(This article belongs to the Special Issue Proteasomes and Cellular Senescence: An Age-Related Connection)
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