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
Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition
Int. J. Mol. Sci. 2024, 25(10), 5297; https://doi.org/10.3390/ijms25105297 (registering DOI) - 13 May 2024
Abstract
Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these
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Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations’ origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia–neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron–glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.
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(This article belongs to the Special Issue The Molecular Research in Brain Development and Cognitive Functions)
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Molecular Insights into Macromolecules Structure, Function, and Regulation
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Zhiwei Yang and Jiasheng Zhao
Int. J. Mol. Sci. 2024, 25(10), 5296; https://doi.org/10.3390/ijms25105296 (registering DOI) - 13 May 2024
Abstract
Macromolecules exhibit ordered structures and complex functions in an aqueous environment with strong thermodynamic fluctuations [...]
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(This article belongs to the Special Issue Molecular Insights into Macromolecules Structure, Function, and Regulation)
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Open AccessReview
Voltage Sensors Embedded in G Protein-Coupled Receptors
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Merav Tauber and Yair Ben-Chaim
Int. J. Mol. Sci. 2024, 25(10), 5295; https://doi.org/10.3390/ijms25105295 (registering DOI) - 13 May 2024
Abstract
Some signaling processes mediated by G protein-coupled receptors (GPCRs) are modulated by membrane potential. In recent years, increasing evidence that GPCRs are intrinsically voltage-dependent has accumulated. A recent publication challenged the view that voltage sensors are embedded in muscarinic receptors. Herein, we briefly
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Some signaling processes mediated by G protein-coupled receptors (GPCRs) are modulated by membrane potential. In recent years, increasing evidence that GPCRs are intrinsically voltage-dependent has accumulated. A recent publication challenged the view that voltage sensors are embedded in muscarinic receptors. Herein, we briefly discuss the evidence that supports the notion that GPCRs themselves are voltage-sensitive proteins and an alternative mechanism that suggests that voltage-gated sodium channels are the voltage-sensing molecules involved in such processes.
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(This article belongs to the Special Issue Cellular Responses to Environmental Changes)
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Open AccessArticle
Toxicity of Large and Small Surface-Engineered Upconverting Nanoparticles for In Vitro and In Vivo Bioapplications
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Lucia Machová Urdzíková, Dana Mareková, Taras Vasylyshyn, Petr Matouš, Vitalii Patsula, Viktoriia Oleksa, Oleksandr Shapoval, Magda Vosmanská, David Liebl, Aleš Benda, Vít Herynek, Daniel Horák and Pavla Jendelová
Int. J. Mol. Sci. 2024, 25(10), 5294; https://doi.org/10.3390/ijms25105294 (registering DOI) - 13 May 2024
Abstract
In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated
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In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.
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(This article belongs to the Special Issue Magnetic Nanoparticles for Biomedical and Imaging Applications 2.0)
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Open AccessPerspective
Dopamine Pharmacodynamics: New Insights
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Fulvio Lauretani, Francesco Giallauria, Crescenzo Testa, Claudia Zinni, Beatrice Lorenzi, Irene Zucchini, Marco Salvi, Raffaele Napoli and Marcello Giuseppe Maggio
Int. J. Mol. Sci. 2024, 25(10), 5293; https://doi.org/10.3390/ijms25105293 (registering DOI) - 13 May 2024
Abstract
Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive
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Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration.
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(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)
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Open AccessEditorial
CRISPR-Cas Systems and Genome Editing: Beginning the Era of CRISPR/Cas Therapies for Humans
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Dmitry S. Karpov
Int. J. Mol. Sci. 2024, 25(10), 5292; https://doi.org/10.3390/ijms25105292 (registering DOI) - 13 May 2024
Abstract
Harnessing of CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated genes) systems for detection, chemical modification, and sequence editing of nucleic acids dramatically changed many fields of fundamental science, biotechnology, and biomedicine [...]
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(This article belongs to the Special Issue CRISPR-Cas Systems and Genome Editing)
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Open AccessReview
Runx2 and Polycystins in Bone Mechanotransduction: Challenges for Therapeutic Opportunities
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Antonios N. Gargalionis, Christos Adamopoulos, Christos T. Vottis, Athanasios G. Papavassiliou and Efthimia K. Basdra
Int. J. Mol. Sci. 2024, 25(10), 5291; https://doi.org/10.3390/ijms25105291 (registering DOI) - 13 May 2024
Abstract
Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development
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Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development and progression of bone loss disorders, but also in the bone-specific aspect of other clinical entities, such as the tumorigenesis of solid organs. Novel treatment options have come into sight that exploit the mechanosensitivity of osteoblasts, osteocytes, and chondrocytes to achieve efficient bone regeneration. In this regard, runt-related transcription factor 2 (Runx2) has emerged as a chief skeletal-specific molecule of differentiation, which is prominent to induction by mechanical stimuli. Polycystins represent a family of mechanosensitive proteins that interact with Runx2 in mechano-induced signaling cascades and foster the regulation of alternative effectors of mechanotransuction. In the present narrative review, we employed a PubMed search to extract the literature concerning Runx2, polycystins, and their association from 2000 to March 2024. The keywords stated below were used for the article search. We discuss recent advances regarding the implication of Runx2 and polycystins in bone remodeling and regeneration and elaborate on the targeting strategies that may potentially be applied for the treatment of patients with bone loss diseases.
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(This article belongs to the Special Issue Cells and Molecules in Bone Remodeling and Repair)
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Open AccessArticle
Clinical Effect of Thioglycosides Extracted from White Mustard on Dental Plaque and Gingivitis: Randomized, Single-Blinded Clinical Trial
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Konrad Michałowski and Aniela Brodzikowska
Int. J. Mol. Sci. 2024, 25(10), 5290; https://doi.org/10.3390/ijms25105290 (registering DOI) - 13 May 2024
Abstract
The antibacterial and anti-inflammatory effect of thioglycosides has already been established. This study investigates the effects of thioglycosides extracted from white mustard, specifically the “Bamberka” variety, in the context of oral hygiene. The aim of the study is to clarify an evidence-based link
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The antibacterial and anti-inflammatory effect of thioglycosides has already been established. This study investigates the effects of thioglycosides extracted from white mustard, specifically the “Bamberka” variety, in the context of oral hygiene. The aim of the study is to clarify an evidence-based link between the documented antibacterial and anti-inflammatory effects attributed to thioglycosides and their practical application in oral care. A randomized, single-blinded (patient-blinded) clinical study was performed on 66 patients using mustard-based toothpaste for oral hygiene. The patients were examined at baseline and after 6 and 12 months. The values of the Approximal Plaque Index (API), the Plaque Index (PI), and Bleeding on probing (BOP) were taken into consideration. The results show a significant reduction in plaque accumulation, especially after 6 months of using mustard-based toothpaste in all examined parameters. This suggests that thioglycosides from mustard contribute to a considerable decrease in dental plaque accumulation, confirming their potential in natural oral care solutions, which is indicated in the main conclusions or interpretations.
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(This article belongs to the Special Issue Natural Products and Oral Health: Challenges and Opportunities)
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Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review
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Luisa Politano
Int. J. Mol. Sci. 2024, 25(10), 5289; https://doi.org/10.3390/ijms25105289 (registering DOI) - 13 May 2024
Abstract
Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the
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Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.
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(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics 2.0)
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Immunological Aspects of Cancer Cell Metabolism
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Sisca Ucche and Yoshihiro Hayakawa
Int. J. Mol. Sci. 2024, 25(10), 5288; https://doi.org/10.3390/ijms25105288 (registering DOI) - 13 May 2024
Abstract
Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells
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Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.
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(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)
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Long-Term Epigenetic Regulation of Foxo3 Expression in Neonatal Valproate-Exposed Rat Hippocampus with Sex-Related Differences
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Eun-Hye Jang and Soon-Ae Kim
Int. J. Mol. Sci. 2024, 25(10), 5287; https://doi.org/10.3390/ijms25105287 (registering DOI) - 13 May 2024
Abstract
Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes
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Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of Foxo3, which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal Foxo3 expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence.
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(This article belongs to the Special Issue Molecular Research in Neurodevelopmental Disorders)
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Open AccessOpinion
Discordant Health Implications and Molecular Mechanisms of Vitamin D in Clinical and Preclinical Studies of Prostate Cancer: A Critical Appraisal of the Literature Data
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Annika Fendler, Carsten Stephan, Bernhard Ralla and Klaus Jung
Int. J. Mol. Sci. 2024, 25(10), 5286; https://doi.org/10.3390/ijms25105286 (registering DOI) - 13 May 2024
Abstract
Clinical and preclinical studies have provided conflicting data on the postulated beneficial effects of vitamin D in patients with prostate cancer. In this opinion piece, we discuss reasons for discrepancies between preclinical and clinical vitamin D studies. Different criteria have been used as
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Clinical and preclinical studies have provided conflicting data on the postulated beneficial effects of vitamin D in patients with prostate cancer. In this opinion piece, we discuss reasons for discrepancies between preclinical and clinical vitamin D studies. Different criteria have been used as evidence for the key roles of vitamin D. Clinical studies report integrative cancer outcome criteria such as incidence and mortality in relation to vitamin D status over time. In contrast, preclinical vitamin D studies report molecular and cellular changes resulting from treatment with the biologically active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol) in tissues. However, these reported changes in preclinical in vitro studies are often the result of treatment with biologically irrelevant high calcitriol concentrations. In typical experiments, the used calcitriol concentrations exceed the calcitriol concentrations in normal and malignant prostate tissue by 100 to 1000 times. This raises reasonable concerns regarding the postulated biological effects and mechanisms of these preclinical vitamin D approaches in relation to clinical relevance. This is not restricted to prostate cancer, as detailed data regarding the tissue-specific concentrations of vitamin D metabolites are currently lacking. The application of unnaturally high concentrations of calcitriol in preclinical studies appears to be a major reason why the results of preclinical in vitro studies hardly match up with outcomes of vitamin D-related clinical studies. Regarding future studies addressing these concerns, we suggest establishing reference ranges of tissue-specific vitamin D metabolites within various cancer entities, carrying out model studies on human cancer cells and patient-derived organoids with biologically relevant calcitriol concentrations, and lastly improving the design of vitamin D clinical trials where results from preclinical studies guide the protocols and endpoints within these trials.
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(This article belongs to the Section Molecular Endocrinology and Metabolism)
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Manganese and Vanadium Co-Exposure Induces Severe Neurotoxicity in the Olfactory System: Relevance to Metal-Induced Parkinsonism
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Hilary Afeseh Ngwa, Alejandra Bargues-Carot, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy and Anumantha G. Kanthasamy
Int. J. Mol. Sci. 2024, 25(10), 5285; https://doi.org/10.3390/ijms25105285 (registering DOI) - 13 May 2024
Abstract
Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn), especially in welding
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Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl2, V2O5, and MnCl2-V2O5 co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl2 (252 µg) alone, V2O5 (182 µg) alone, or a mixture of MnCl2 (252 µg) and V2O5 (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.
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(This article belongs to the Special Issue Toxicity Mechanism of Emerging Pollutants)
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Open AccessCommunication
No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients
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Andrzej Dmytrzak, Klaudyna Lewandowska, Agnieszka Boroń, Beata Łoniewska, Natalie Grzesch, Andrzej Brodkiewicz, Jeremy S. C. Clark, Andrzej Ciechanowicz and Dorota Kostrzewa-Nowak
Int. J. Mol. Sci. 2024, 25(10), 5284; https://doi.org/10.3390/ijms25105284 (registering DOI) - 13 May 2024
Abstract
A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of
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A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.
Full article
(This article belongs to the Special Issue The Role of Cytokines in Diseases)
Open AccessArticle
Experimental and Computational Studies on the Interaction of DNA with Hesperetin Schiff Base CuII Complexes
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Federico Pisanu, Anna Sykula, Giuseppe Sciortino, Feliu Maseras, Elzbieta Lodyga-Chruscinska and Eugenio Garribba
Int. J. Mol. Sci. 2024, 25(10), 5283; https://doi.org/10.3390/ijms25105283 (registering DOI) - 13 May 2024
Abstract
The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3)
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The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3) and their CuII complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLnH2(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV–Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants (Kb) of the Cu compounds with CT-DNA, in the range (2.3–9.2) × 106, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π–π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LnH2)(AcO)] and [Cu(LnH2)(H2O)]+, the tautomer that binds CuII, amido (am) and not imido (im), and the coordination mode of HTSC (O−, N, S), instead of (O−, N, NH2). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(L1H2am)(AcO)] > [Cu(L2H2am)(AcO)] ≈ TO ≈ L1H3 > [Cu(L3H2am)(AcO)], in line with the experimental Kb constants, obtained from the UV–Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(L1H2am)(AcO)] is larger than [Cu(L1H2am)(H2O)]+. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.
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(This article belongs to the Special Issue Recent Advances in Coordination Chemistry of Metal Complexes Based on Schiff Base Ligands: Structure-Property Relationships and Applications, 2nd Edition)
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Open AccessEditorial
Special Issue “Ovarian Cancer: Advances on Pathophysiology and Therapies”
by
Giovanni Tossetta and Annalisa Inversetti
Int. J. Mol. Sci. 2024, 25(10), 5282; https://doi.org/10.3390/ijms25105282 (registering DOI) - 13 May 2024
Abstract
Ovarian cancer is a gynecologic cancer with a high mortality rate, and its incidence has increased significantly over the past 50 years [...]
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(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)
Open AccessArticle
Microscopic Analysis of Nuclear Speckles in a Viviparous Reptile
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Jeniffer Acosta-Cárdenas, Luis Felipe Jiménez-García, Sarai de Jesús Cruz-Gómez, Ana Paulina Mendoza-von der Borch and María de Lourdes Segura-Valdez
Int. J. Mol. Sci. 2024, 25(10), 5281; https://doi.org/10.3390/ijms25105281 (registering DOI) - 12 May 2024
Abstract
Nuclear speckles are compartments enriched in splicing factors present in the nucleoplasm of eucaryote cells. Speckles have been studied in mammalian culture and tissue cells, as well as in some non-mammalian vertebrate cells and invertebrate oocytes. In mammals, their morphology is linked to
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Nuclear speckles are compartments enriched in splicing factors present in the nucleoplasm of eucaryote cells. Speckles have been studied in mammalian culture and tissue cells, as well as in some non-mammalian vertebrate cells and invertebrate oocytes. In mammals, their morphology is linked to the transcriptional and splicing activities of the cell through a recruitment mechanism. In rats, speckle morphology depends on the hormonal cycle. In the present work, we explore whether a similar situation is also present in non-mammalian cells during the reproductive cycle. We studied the speckled pattern in several tissues of a viviparous reptile, the lizard Sceloporus torquatus, during two different stages of reproduction. We used immunofluorescence staining against splicing factors in hepatocytes and oviduct epithelium cells and fluorescence and confocal microscopy, as well as ultrastructural immunolocalization and EDTA contrast in Transmission Electron Microscopy. The distribution of splicing factors in the nucleoplasm of oviductal cells and hepatocytes coincides with the nuclear-speckled pattern described in mammals. Ultrastructurally, those cell types display Interchromatin Granule Clusters and Perichromatin Fibers. In addition, the morphology of speckles varies in oviduct cells at the two stages of the reproductive cycle analyzed, paralleling the phenomenon observed in the rat. The results show that the morphology of speckles in reptile cells depends upon the reproductive stage as it occurs in mammals.
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(This article belongs to the Special Issue Recent Research on Cell and Molecular Biology)
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A Nuclear Magnetic Resonance (NMR)- and Mass Spectrometry (MS)-Based Saturation Kinetics Model of a Bryophyllum pinnatum Decoction as a Treatment for Kidney Stones
by
Candus Chik, Anne-Laure Larroque, Yuan Zhuang, Shane Feinstein, Donald L. Smith, Sero Andonian, Aimee K. Ryan, Bertrand Jean-Claude and Indra R. Gupta
Int. J. Mol. Sci. 2024, 25(10), 5280; https://doi.org/10.3390/ijms25105280 (registering DOI) - 12 May 2024
Abstract
Bryophyllum pinnatum (BP) is a medicinal plant used to treat many conditions when taken as a leaf juice, leaves in capsules, as an ethanolic extract, and as herbal tea. These preparations have been chemically analyzed except for decoctions derived from boiled green leaves.
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Bryophyllum pinnatum (BP) is a medicinal plant used to treat many conditions when taken as a leaf juice, leaves in capsules, as an ethanolic extract, and as herbal tea. These preparations have been chemically analyzed except for decoctions derived from boiled green leaves. In preparation for a clinical trial to validate BP tea as a treatment for kidney stones, we used NMR and MS analyses to characterize the saturation kinetics of the release of metabolites. During boiling of the leaves, (a) the pH decreased to 4.8 within 14 min and then stabilized; (b) regarding organic acids, citric and malic acid were released with maximum release time (tmax) = 35 min; (c) for glycoflavonoids, quercetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside (Q-3O-ArRh), myricetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside (M-3O-ArRh), kappinatoside, myricitrin, and quercitrin were released with tmax = 5–10 min; and (d) the total phenolic content (TPC) and the total antioxidant capacity (TAC) reached a tmax at 55 min and 61 min, respectively. In summary, 24 g of leaves boiled in 250 mL of water for 61 min ensures a maximal release of key water-soluble metabolites, including organic acids and flavonoids. These metabolites are beneficial for treating kidney stones because they target oxidative stress and inflammation and inhibit stone formation.
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(This article belongs to the Special Issue Bioactives in Fruit and Vegetables)
Open AccessArticle
Regulation of Glutathione S-Transferase Omega 1 Mediated by Cysteine Residues Sensing the Redox Environment
by
Kwonyoung Kim, Jeongin Choi, Sana Iram and Jihoe Kim
Int. J. Mol. Sci. 2024, 25(10), 5279; https://doi.org/10.3390/ijms25105279 (registering DOI) - 12 May 2024
Abstract
Glutathione S-transferase omega 1 (GstO1) catalyzes deglutathionylation and plays an important role in the protein glutathionylation cycle in cells. GstO1 contains four conserved cysteine residues (C32, C90, C191, C236) found to be mutated in patients with associated diseases. In this study, we
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Glutathione S-transferase omega 1 (GstO1) catalyzes deglutathionylation and plays an important role in the protein glutathionylation cycle in cells. GstO1 contains four conserved cysteine residues (C32, C90, C191, C236) found to be mutated in patients with associated diseases. In this study, we investigated the effects of cysteine mutations on the structure and function of GstO1 under different redox conditions. Wild-type GstO1 (WT) was highly sensitive to hydrogen peroxide (H2O2), which caused precipitation and denaturation at a physiological temperature. However, glutathione efficiently inhibited the H2O2-induced denaturation of GstO1. Cysteine mutants C32A and C236A exhibited redox-dependent stabilities and enzyme activities significantly different from those of WT. These results indicate that C32 and C236 play critical roles in GstO1 regulation by sensing redox environments and explain the pathological effect of cysteine mutations found in patients with associated diseases.
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(This article belongs to the Section Biochemistry)
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Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis and Goodpasture Syndrome
by
Evangelia Fouka, Fotios Drakopanagiotakis and Paschalis Steiropoulos
Int. J. Mol. Sci. 2024, 25(10), 5278; https://doi.org/10.3390/ijms25105278 (registering DOI) - 12 May 2024
Abstract
Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing
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Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. Furthermore, the impact of genetic predisposition and environmental factors on disease susceptibility and severity was considered, and the current treatment options were presented. Understanding the mechanisms involved in the pathogenesis of pulmonary vasculitis is crucial for developing targeted therapies and improving clinical outcomes in affected individuals.
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(This article belongs to the Special Issue Forward in Vasculitis: Genetics and Beyond)
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