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
Micronutrient Status and Breast Cancer: A Narrative Review
Int. J. Mol. Sci. 2024, 25(9), 4968; https://doi.org/10.3390/ijms25094968 (registering DOI) - 02 May 2024
Abstract
Breast cancer is one of the most common cancers worldwide, at the same time being one of the most prevalent causes of women’s death. Many factors such as alcohol, weight fluctuations, or hormonal replacement therapy can potentially contribute to breast cancer development and
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Breast cancer is one of the most common cancers worldwide, at the same time being one of the most prevalent causes of women’s death. Many factors such as alcohol, weight fluctuations, or hormonal replacement therapy can potentially contribute to breast cancer development and progression. Another important factor in breast cancer onset includes micronutrient status. In this narrative review, we analyzed 23 micronutrients and their possible influence on breast cancer onset and progression. Further, the aim of this study was to investigate the impact of micronutrient status on the prevention of breast cancer and its possible influence on various therapeutic pathways. We researched meta-analyses, systemic and narrative reviews, retrospective studies, as well as original studies on human and animal models. The results of these studies indicate a possible correlation between the different levels of micronutrients and a decreased risk of breast cancer as well as a better survival rate. However, further studies are necessary to establish adequate doses of supplementation of the chosen micronutrients and the exact mechanisms of micronutrient impact on breast cancer therapy.
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(This article belongs to the Special Issue Molecular Advances in Gynecologic Cancer)
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Age Prediction Using DNA Methylation Heterogeneity Metrics
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Dmitry I. Karetnikov, Stanislav E. Romanov, Vladimir P. Baklaushev and Petr P. Laktionov
Int. J. Mol. Sci. 2024, 25(9), 4967; https://doi.org/10.3390/ijms25094967 (registering DOI) - 02 May 2024
Abstract
Dynamic changes in genomic DNA methylation patterns govern the epigenetic developmental programs and accompany the organism's aging. Epigenetic clock (eAge) algorithms utilize DNA methylation to estimate the age and risk factors for diseases as well as analyze the impact of various interventions. High-throughput
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Dynamic changes in genomic DNA methylation patterns govern the epigenetic developmental programs and accompany the organism's aging. Epigenetic clock (eAge) algorithms utilize DNA methylation to estimate the age and risk factors for diseases as well as analyze the impact of various interventions. High-throughput bisulfite sequencing methods, such as reduced-representation bisulfite sequencing (RRBS) or whole genome bisulfite sequencing (WGBS), provide an opportunity to identify the genomic regions of disordered or heterogeneous DNA methylation, which might be associated with cell-type heterogeneity, DNA methylation erosion, and allele-specific methylation. We systematically evaluated the applicability of five scores assessing the variability of methylation patterns by evaluating within-sample heterogeneity (WSH) to construct human blood epigenetic clock models using RRBS data. The best performance was demonstrated by the model based on a metric designed to assess DNA methylation erosion with an MAE of 3.686 years. We also trained a prediction model that uses the average methylation level over genomic regions. Although this region-based model was relatively more efficient than the WSH-based model, the latter required the analysis of just a few short genomic regions and, therefore, could be a useful tool to design a reduced epigenetic clock that is analyzed by targeted next-generation sequencing.
Full article
(This article belongs to the Special Issue New Advances in Genetics and Epigenetics of Aging)
Open AccessArticle
In Vitro Effect of 9,9′-Norharmane Dimer against Herpes Simplex Viruses
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María Micaela Gonzalez, Maria Guadalupe Vizoso-Pinto, Rosa Erra-Balsells, Thomas Gensch and Franco M. Cabrerizo
Int. J. Mol. Sci. 2024, 25(9), 4966; https://doi.org/10.3390/ijms25094966 (registering DOI) - 02 May 2024
Abstract
Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to
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Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9′-norharmane dimer (nHo-dimer), which belongs to the β-carboline (βC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.
Full article
(This article belongs to the Special Issue Antivirals and Vaccines: Molecular Research in Treatment and Prevention)
Open AccessArticle
Structural and Immunological Features of PR-10 Allergens: Focusing on the Major Alder Pollen Allergen Aln g 1
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Daria N. Melnikova, Ekaterina I. Finkina, Andrey E. Potapov, Yulia D. Danilova, Ilia Y. Toropygin, Natalia S. Matveevskaya, Tatiana V. Ovchinnikova and Ivan V. Bogdanov
Int. J. Mol. Sci. 2024, 25(9), 4965; https://doi.org/10.3390/ijms25094965 (registering DOI) - 02 May 2024
Abstract
Today, allergies have become a serious problem. PR-10 proteins are clinically relevant allergens that have the ability to bind hydrophobic ligands, which can significantly increase their allergenicity potential. It has been recently shown that not only the birch pollen allergen Bet v 1
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Today, allergies have become a serious problem. PR-10 proteins are clinically relevant allergens that have the ability to bind hydrophobic ligands, which can significantly increase their allergenicity potential. It has been recently shown that not only the birch pollen allergen Bet v 1 but also the alder pollen allergen Aln g 1, might act as a true sensitizer of the immune system. The current investigation is aimed at the further study of the allergenic and structural features of Aln g 1. By using qPCR, we showed that Aln g 1 was able to upregulate alarmins in epithelial cells, playing an important role in sensitization. With the use of CD-spectroscopy and ELISA assays with the sera of allergic patients, we demonstrated that Aln g 1 did not completely restore its structure after thermal denaturation, which led to a decrease in its IgE-binding capacity. Using site-directed mutagenesis, we revealed that the replacement of two residues (Asp27 and Leu30) in the structure of Aln g 1 led to a decrease in its ability to bind to both IgE from sera of allergic patients and lipid ligands. The obtained data open a prospect for the development of hypoallergenic variants of the major alder allergen Aln g 1 for allergen-specific immunotherapy.
Full article
(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Allergic Reactions)
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Open AccessArticle
Impact of the Oral Administration of Polystyrene Microplastics on Hepatic Lipid, Glucose, and Amino Acid Metabolism in C57BL/6Korl and C57BL/6-Lepem1hwl/Korl Mice
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Yujeong Roh, Jieun Kim, Heejin Song, Ayun Seol, Taeryeol Kim, Eunseo Park, Kiho Park, Sujeong Lim, Suha Wang, Youngsuk Jung, Hyesung Kim, Yong Lim and Daeyoun Hwang
Int. J. Mol. Sci. 2024, 25(9), 4964; https://doi.org/10.3390/ijms25094964 (registering DOI) - 02 May 2024
Abstract
The impact of microplastics (MPs) on the metabolic functions of the liver is currently unclear and not completely understood. To investigate the effects of the administration of MPs on the hepatic metabolism of normal and obese mice, alterations in the lipid, glucose (Glu),
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The impact of microplastics (MPs) on the metabolic functions of the liver is currently unclear and not completely understood. To investigate the effects of the administration of MPs on the hepatic metabolism of normal and obese mice, alterations in the lipid, glucose (Glu), and amino acid regulation pathways were analyzed in the liver and adipose tissues of C57BL/6Korl (wild type, WT) or C57BL/6-Lepem1hwl/Korl mice (leptin knockout, Lep KO) orally administered polystyrene (PS) MPs for 9 weeks. Significant alterations in the lipid accumulation, adipogenesis, lipogenesis, and lipolysis pathways were detected in the liver tissue of MP-treated WT and Lep KO mice compared to the vehicle-treated group. These alterations in their liver tissues were accompanied by an upregulation of the serum lipid profile, as well as alterations in the adipogenesis, lipogenesis, and lipolysis pathways in the adipose tissues of MP-treated WT and Lep KO mice. Specifically, the level of leptin was increased in the adipose tissues of MP-treated WT mice without any change in their food intake. Also, MP-induced disruptions in the glycogenolysis, Glu transporter type 4 (GLUT4)-5′ AMP-activated protein kinase (AMPK) signaling pathway, levels of lipid intermediates, and the insulin resistance of the liver tissues of WT and Lep KO mice were observed. Furthermore, the levels of seven endogenous metabolites were remarkably changed in the serum of WT and Lep KO mice after MP administrations. Finally, the impact of the MP administration observed in both types of mice was further verified in differentiated 3T3-L1 adipocytes and HepG2 cells. Thus, these results suggest that the oral administration of MPs for 9 weeks may be associated with the disruption of lipid, Glu, and amino acid metabolism in the liver tissue of obese WT and Lep KO mice.
Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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Open AccessArticle
A Fruit-Expressed MYB Transcription Factor Regulates Anthocyanin Biosynthesis in Atropa belladonna
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Xiaoqiang Liu, Tengfei Zhao, Lina Yuan, Fei Qiu, Yueli Tang, Dan Li, Fangyuan Zhang, Lingjiang Zeng, Chunxian Yang, Mohammad Mahmoud Nagdy, Zun Lai Lai Htun, Xiaozhong Lan, Min Chen, Zhihua Liao and Yan Li
Int. J. Mol. Sci. 2024, 25(9), 4963; https://doi.org/10.3390/ijms25094963 (registering DOI) - 02 May 2024
Abstract
Anthocyanins are water-soluble flavonoid pigments that play a crucial role in plant growth and metabolism. They serve as attractants for animals by providing plants with red, blue, and purple pigments, facilitating pollination and seed dispersal. The fruits of solanaceous plants, tomato (Solanum
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Anthocyanins are water-soluble flavonoid pigments that play a crucial role in plant growth and metabolism. They serve as attractants for animals by providing plants with red, blue, and purple pigments, facilitating pollination and seed dispersal. The fruits of solanaceous plants, tomato (Solanum lycopersicum) and eggplant (Solanum melongena), primarily accumulate anthocyanins in the fruit peels, while the ripe fruits of Atropa belladonna (Ab) have a dark purple flesh due to anthocyanin accumulation. In this study, an R2R3-MYB transcription factor (TF), AbMYB1, was identified through association analysis of gene expression and anthocyanin accumulation in different tissues of A. belladonna. Its role in regulating anthocyanin biosynthesis was investigated through gene overexpression and RNA interference (RNAi). Overexpression of AbMYB1 significantly enhanced the expression of anthocyanin biosynthesis genes, such as AbF3H, AbF3′5′H, AbDFR, AbANS, and Ab3GT, leading to increased anthocyanin production. Conversely, RNAi-mediated suppression of AbMYB1 resulted in decreased expression of most anthocyanin biosynthesis genes, as well as reduced anthocyanin contents in A. belladonna. Overall, AbMYB1 was identified as a fruit-expressed R2R3-MYB TF that positively regulated anthocyanin biosynthesis in A. belladonna. This study provides valuable insights into the regulation of anthocyanin biosynthesis in Solanaceae plants, laying the foundation for understanding anthocyanin accumulation especially in the whole fruits of solanaceous plants.
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(This article belongs to the Special Issue Plant Omics: Sensing, Signaling, Regulation and Homeostasis)
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Open AccessArticle
BAP31 Plays an Essential Role in Mouse B Cell Development via Regulation of BCR Signaling
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Bo Zhao, Fei An, Zhenzhen Hao, Wanting Zhang and Bing Wang
Int. J. Mol. Sci. 2024, 25(9), 4962; https://doi.org/10.3390/ijms25094962 (registering DOI) - 02 May 2024
Abstract
B cell receptor-associated protein 31 (BAP31) is a transmembrane protein that is widely expressed and primarily located in the endoplasmic reticulum (ER). B cells play a crucial role in the immune system, and BAP31 significantly contributes to the functions of various immune cells.
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B cell receptor-associated protein 31 (BAP31) is a transmembrane protein that is widely expressed and primarily located in the endoplasmic reticulum (ER). B cells play a crucial role in the immune system, and BAP31 significantly contributes to the functions of various immune cells. However, the specific role of BAP31 in B lymphocytes development remains unknown. In this study, we utilized a mouse model with BAP31 deleted from B cells to investigate its effects. Our findings reveal a block in early B cell development in the bone marrow and a significant decrease in the number of B cells in peripheral lymphoid organs taken from BAP31 B cell conditional knockout (BAP31-BCKO) mice. B cell receptor (BCR) signaling is crucial for the normal development and differentiation of B lymphocytes. BAP31, an endoplasmic reticulum membrane protein, directly regulates the BCR signaling pathway and was shown to be significantly positively correlated with B cell activation and proliferation. These findings establish BAP31 as a crucial regulator of early B cell development.
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(This article belongs to the Section Molecular Immunology)
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Comparative Transcriptomic Analysis of WSSV-Challenged Penaeus vannamei with Variable Resistance Levels
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Xupeng Li, Qian Xue, Sheng Luan, Kun Luo, Jie Kong and Xianhong Meng
Int. J. Mol. Sci. 2024, 25(9), 4961; https://doi.org/10.3390/ijms25094961 (registering DOI) - 02 May 2024
Abstract
The Pacific white shrimp, Penaeus vannamei, is highly susceptible to white spot syndrome virus (WSSV). Our study explored the transcriptomic responses of P. vannamei from resistant and susceptible families, uncovering distinct expression patterns after WSSV infection. The analysis revealed a higher
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The Pacific white shrimp, Penaeus vannamei, is highly susceptible to white spot syndrome virus (WSSV). Our study explored the transcriptomic responses of P. vannamei from resistant and susceptible families, uncovering distinct expression patterns after WSSV infection. The analysis revealed a higher number of differentially expressed genes (DEGs) in the susceptible family following WSSV infection compared to the resistant family, when both were evaluated against their respective control groups, indicating that the host resistance of the family line influences the transcriptome. The results also showed that subsequent to an identical duration following WSSV infection, there were more DEGs in P. vannamei with a high viral load than in those with a low viral load. To identify common transcriptomic responses, we profiled DEGs across families at 96 and 228 h post-infection (hpi). The analysis yielded 64 up-regulated and 37 down-regulated DEGs at 96 hpi, with 33 up-regulated and 34 down-regulated DEGs at 228 hpi, showcasing the dynamics of the transcriptomic response over time. Real-time RT-PCR assays confirmed significant DEG expression changes post-infection. Our results offer new insights into shrimp’s molecular defense mechanisms against WSSV.
Full article
(This article belongs to the Special Issue Aquatic Biotechnology and Its Application in Genetic Breeding)
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Open AccessReview
On the Re-Creation of Protoribosome Analogues in the Lab
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Ilana Agmon
Int. J. Mol. Sci. 2024, 25(9), 4960; https://doi.org/10.3390/ijms25094960 (registering DOI) - 02 May 2024
Abstract
The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous emergence of a protoribosome capable of catalyzing the synthesis of the initial peptides. The peptidyl transferase center (PTC)
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The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous emergence of a protoribosome capable of catalyzing the synthesis of the initial peptides. The peptidyl transferase center (PTC) region in the modern ribosomal large subunit is believed to retain a vestige of such a prebiotic non-coded protoribosome, which would have self-assembled from random RNA chains, catalyzed peptide bond formation between arbitrary amino acids, and produced short peptides. Recently, three research groups experimentally demonstrated that several distinct dimeric constructs of protoribosome analogues, derived predicated on the approximate 2-fold rotational symmetry inherent in the PTC region, possess the ability to spontaneously fold, dimerize, and catalyze the formation of peptide bonds and of short peptides. These dimers are examined, aiming at retrieving information concerned with the characteristics of a prebiotic protoribosome. The analysis suggests preconditions for the laboratory re-creation of credible protoribosome analogues, including the preference of a heterodimer protoribosome, contradicting the common belief in the precedence of homodimers. Additionally, it derives a dynamic process which possibly played a role in the spontaneous production of the first bio-catalyzed peptides in the prebiotic world.
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(This article belongs to the Section Biochemistry)
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SGLT2 Inhibitors in Kidney Diseases—A Narrative Review
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Agata Gajewska, Jakub Wasiak, Natalia Sapeda, Ewelina Młynarska, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2024, 25(9), 4959; https://doi.org/10.3390/ijms25094959 - 01 May 2024
Abstract
Some of the most common conditions affecting people are kidney diseases. Among them, we distinguish chronic kidney disease and acute kidney injury. Both entities pose serious health risks, so new drugs are still being sought to treat and prevent them. In recent years,
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Some of the most common conditions affecting people are kidney diseases. Among them, we distinguish chronic kidney disease and acute kidney injury. Both entities pose serious health risks, so new drugs are still being sought to treat and prevent them. In recent years, such a role has begun to be assigned to sodium-glucose cotransporter-2 (SGLT2) inhibitors. They increase the amount of glucose excreted in the urine. For this reason, they are currently used as a first-line drug in type 2 diabetes mellitus. Due to their demonstrated cardioprotective effect, they are also used in heart failure treatment. As for the renal effects of SGLT2 inhibitors, they reduce intraglomerular pressure and decrease albuminuria. This results in a slower decline in glomelular filtration rate (GFR) in patients with kidney disease. In addition, these drugs have anti-inflammatory and antifibrotic effects. In the following article, we review the evidence for the effectiveness of this group of drugs in kidney disease and their nephroprotective effect. Further research is still needed, but meta-analyses indicate SGLT2 inhibitors' efficacy in kidney disease, especially the one caused by diabetes. Development of new drugs and clinical trials on specific patient subgroups will further refine their nephroprotective effects.
Full article
(This article belongs to the Special Issue New Insights into Kidney Diseases)
Open AccessReview
Use of Statins in Heart Failure with Preserved Ejection Fraction: Current Evidence and Perspectives
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Artem Ovchinnikov, Alexandra Potekhina, Tatiana Arefieva, Anastasiia Filatova, Fail Ageev and Evgeny Belyavskiy
Int. J. Mol. Sci. 2024, 25(9), 4958; https://doi.org/10.3390/ijms25094958 - 01 May 2024
Abstract
Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and
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Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and may be beneficial in HF, especially in HFpEF. Numerous observational clinical trials have consistently shown a beneficial prognostic effect of statins in patients with HFpEF, while the results of two larger trials in patients with HFrEF have been controversial. Such differences may be related to a more pronounced impact of the pleiotropic properties of statins on the pathophysiology of HFpEF and pro-inflammatory comorbidities (arterial hypertension, diabetes mellitus, obesity, chronic kidney disease) that are more common in HFpEF. This review discusses the potential mechanisms of statin action that may be beneficial for patients with HFpEF, as well as clinical trials that have evaluated the statin effects on left ventricular diastolic function and clinical outcomes in patients with HFpEF.
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(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)
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The ZmbHLH47-ZmSnRK2.9 Module Promotes Drought Tolerance in Maize
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Zhenwei Yan, Fajun Zhang, Chunhua Mu, Changle Ma, Guoqi Yao, Yue Sun, Jing Hou, Bingying Leng and Xia Liu
Int. J. Mol. Sci. 2024, 25(9), 4957; https://doi.org/10.3390/ijms25094957 - 01 May 2024
Abstract
Drought stress globally poses a significant threat to maize (Zea mays L.) productivity and the underlying molecular mechanisms of drought tolerance remain elusive. In this study, we characterized ZmbHLH47, a basic helix–loop–helix (bHLH) transcription factor, as a positive regulator of drought tolerance
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Drought stress globally poses a significant threat to maize (Zea mays L.) productivity and the underlying molecular mechanisms of drought tolerance remain elusive. In this study, we characterized ZmbHLH47, a basic helix–loop–helix (bHLH) transcription factor, as a positive regulator of drought tolerance in maize. ZmbHLH47 expression was notably induced by both drought stress and abscisic acid (ABA). Transgenic plants overexpressing ZmbHLH47 displayed elevated drought tolerance and ABA responsiveness, while the zmbhlh47 mutant exhibited increased drought sensitivity and reduced ABA sensitivity. Mechanistically, it was revealed that ZmbHLH47 could directly bind to the promoter of ZmSnRK2.9 gene, a member of the subgroup III SnRK2 kinases, activating its expression. Furthermore, ZmSnRK2.9-overexpressing plants exhibited enhanced ABA sensitivity and drought tolerance, whereas the zmsnrk2.9 mutant displayed a decreased sensitivity to both. Notably, overexpressing ZmbHLH47 in the zmsnrk2.9 mutant closely resembled the zmsnrk2.9 mutant, indicating the importance of the ZmbHLH47-ZmSnRK2.9 module in ABA response and drought tolerance. These findings provided valuable insights and a potential genetic resource for enhancing the environmental adaptability of maize.
Full article
(This article belongs to the Special Issue Advance in Plant Abiotic Stress)
Open AccessReview
How We Interpret Thrombosis with Thrombocytopenia Syndrome?
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Shinya Yamada and Hidesaku Asakura
Int. J. Mol. Sci. 2024, 25(9), 4956; https://doi.org/10.3390/ijms25094956 - 01 May 2024
Abstract
Platelets play an important role in hemostasis, and a low platelet count usually increases the risk of bleeding. Conditions in which thrombosis occurs despite low platelet counts are referred to as thrombosis with thrombocytopenia syndrome, including heparin-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, paroxysmal
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Platelets play an important role in hemostasis, and a low platelet count usually increases the risk of bleeding. Conditions in which thrombosis occurs despite low platelet counts are referred to as thrombosis with thrombocytopenia syndrome, including heparin-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, thrombotic microangiopathy (TMA), and disseminated intravascular coagulation. TMA includes thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (HUS), and atypical HUS. Patients with these pathologies present with thrombosis and consumptive thrombocytopenia associated with the activation of platelets and the coagulation system. Treatment varies from disease to disease, and many diseases have direct impacts on mortality and organ prognosis if therapeutic interventions are not promptly implemented. Underlying diseases and the results of physical examinations and general laboratory tests as part of a thorough workup for patients should promptly lead to therapeutic intervention before definitive diagnosis. For some diseases, the diagnosis and initial treatment must proceed in parallel. Utilization of not only laboratory tests but also various scoring systems is important for validating therapeutic interventions based on clinical information.
Full article
(This article belongs to the Special Issue Molecular Immunology in Hematological Disorders 2.0)
Open AccessArticle
Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking
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Grace Gupta and Gennady Verkhivker
Int. J. Mol. Sci. 2024, 25(9), 4955; https://doi.org/10.3390/ijms25094955 - 01 May 2024
Abstract
Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike
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Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike proteins are associated with the diversity of cryptic allosteric sites and complex molecular mechanisms that can be employed by allosteric ligands, including the alteration of the conformational equilibrium of spike protein and preferential stabilization of specific functional states. In the current study, we combine conformational dynamics analysis of distinct forms of the full-length spike protein trimers and machine-learning-based binding pocket detection with the ensemble-based ligand docking and binding free energy analysis to characterize the potential allosteric binding sites and determine structural and energetic determinants of allosteric inhibition for a series of experimentally validated allosteric molecules. The results demonstrate a good agreement between computational and experimental binding affinities, providing support to the predicted binding modes and suggesting key interactions formed by the allosteric ligands to elicit the experimentally observed inhibition. We establish structural and energetic determinants of allosteric binding for the experimentally known allosteric molecules, indicating a potential mechanism of allosteric modulation by targeting the hinges of the inter-protomer movements and blocking conformational changes between the closed and open spike trimer forms. The results of this study demonstrate that combining ensemble-based ligand docking with conformational states of spike protein and rigorous binding energy analysis enables robust characterization of the ligand binding modes, the identification of allosteric binding hotspots, and the prediction of binding affinities for validated allosteric modulators, which is consistent with the experimental data. This study suggested that the conformational adaptability of the protein allosteric sites and the diversity of ligand bound conformations are both in play to enable efficient targeting of allosteric binding sites and interfere with the conformational changes.
Full article
(This article belongs to the Special Issue Computational Pharmacology in Drug Discovery)
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Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype
by
Ha-Young Kim, Jung-Hee Shim, Baek-Kyu Kim and Chan-Yeong Heo
Int. J. Mol. Sci. 2024, 25(9), 4954; https://doi.org/10.3390/ijms25094954 - 01 May 2024
Abstract
Fibrous dysplasia (FD) poses a therapeutic challenge due to the dysregulated extracellular matrix (ECM) accumulation within affected bone tissues. In this study, we investigate the therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in managing FD by examining its effects on
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Fibrous dysplasia (FD) poses a therapeutic challenge due to the dysregulated extracellular matrix (ECM) accumulation within affected bone tissues. In this study, we investigate the therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in managing FD by examining its effects on FD-derived cells in vitro. Our findings demonstrate that 1,25(OH)2D3 treatment attenuates the pro-fibrotic phenotype of FD-derived cells by suppressing the expression of key pro-fibrotic markers and inhibiting cell proliferation and migration. Moreover, 1,25(OH)2D3 enhances mineralization by attenuating pre-osteoblastic cellular hyperactivity and promoting maturation towards an osteocytic phenotype. These results offer valuable insights into potential treatments for FD, highlighting the role of 1,25(OH)2D3 in modulating the pathological properties of FD-derived cells.
Full article
(This article belongs to the Special Issue Application of Natural Products in Prevention of Bone Related Diseases)
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DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4
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Bingbing Feng, Xinying Wang, Ding Qiu, Haiyang Sun, Jianping Deng, Ying Tan, Kaile Ji, Shaoting Xu, Shuishen Zhang and Ce Tang
Int. J. Mol. Sci. 2024, 25(9), 4953; https://doi.org/10.3390/ijms25094953 - 01 May 2024
Abstract
Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been
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Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.
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(This article belongs to the Section Molecular Oncology)
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Open AccessEditorial
Chemistry and Biology of Noncanonical Nucleic Acid Structures: From Physicochemical Properties to Therapeutic Applications
by
Jussara Amato, Antonio Randazzo and Bruno Pagano
Int. J. Mol. Sci. 2024, 25(9), 4952; https://doi.org/10.3390/ijms25094952 - 01 May 2024
Abstract
The aim of this Special Issue is to highlight significant and new aspects concerning the chemistry and biology of noncanonical nucleic acid structures, with emphasis on their structure, stability, and conformational equilibria, as well as on the biological relevance of their interactions with
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The aim of this Special Issue is to highlight significant and new aspects concerning the chemistry and biology of noncanonical nucleic acid structures, with emphasis on their structure, stability, and conformational equilibria, as well as on the biological relevance of their interactions with proteins and ligands [...]
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(This article belongs to the Special Issue Chemistry and Biology of Noncanonical Nucleic Acid Structures: From Physicochemical Properties to Therapeutic Applications)
Open AccessEditorial
Role of Bioactives in Neurodegenerative Diseases
by
Lefteris C. Zacharia
Int. J. Mol. Sci. 2024, 25(9), 4951; https://doi.org/10.3390/ijms25094951 - 01 May 2024
Abstract
Neurodegenerative diseases (NDs) affect millions worldwide, with the two most prevalent being Alzheimer’s and Parkinson disease [...]
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(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)
Open AccessCommunication
Lactate Dehydrogenase-Elevating Virus Infection Inhibits MOG Peptide Presentation by CD11b+CD11c+ Dendritic Cells in a Mouse Model of Multiple Sclerosis
by
Pyone Pyone Soe, Mélanie Gaignage, Mohamed F. Mandour, Etienne Marbaix, Jacques Van Snick and Jean-Paul Coutelier
Int. J. Mol. Sci. 2024, 25(9), 4950; https://doi.org/10.3390/ijms25094950 - 01 May 2024
Abstract
Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized
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Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35–55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.
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(This article belongs to the Special Issue Animal Research Model for Neurological Diseases)
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Open AccessArticle
Thymol, a Monoterpenoid within Polymeric Iodophor Formulations and Their Antimicrobial Activities
by
Zehra Edis and Samir Haj Bloukh
Int. J. Mol. Sci. 2024, 25(9), 4949; https://doi.org/10.3390/ijms25094949 - 01 May 2024
Abstract
Antimicrobial resistance (AMR) poses an emanating threat to humanity’s future. The effectiveness of commonly used antibiotics against microbial infections is declining at an alarming rate. As a result, morbidity and mortality rates are soaring, particularly among immunocompromised populations. Exploring alternative solutions, such as
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Antimicrobial resistance (AMR) poses an emanating threat to humanity’s future. The effectiveness of commonly used antibiotics against microbial infections is declining at an alarming rate. As a result, morbidity and mortality rates are soaring, particularly among immunocompromised populations. Exploring alternative solutions, such as medicinal plants and iodine, shows promise in combating resistant pathogens. Such antimicrobials could effectively inhibit microbial proliferation through synergistic combinations. In our study, we prepared a formulation consisting of Aloe barbadensis Miller (AV), Thymol, iodine (I2), and polyvinylpyrrolidone (PVP). Various analytical methods including SEM/EDS, UV-vis, Raman, FTIR, and XRD were carried out to verify the purity, composition, and morphology of AV-PVP-Thymol-I2. We evaluated the inhibitory effects of this formulation against 10 selected reference strains using impregnated sterile discs, surgical sutures, gauze bandages, surgical face masks, and KN95 masks. The antimicrobial properties of AV-PVP-Thymol-I2 were assessed through disc diffusion methods against 10 reference strains in comparison with two common antibiotics. The 25-month-old formulation exhibited slightly lower inhibitory zones, indicating changes in the sustained-iodine-release reservoir. Our findings confirm AV-PVP-Thymol-I2 as a potent antifungal and antibacterial agent against the reference strains, demonstrating particularly strong inhibitory action on surgical sutures, cotton bandages, and face masks. These results enable the potential use of the formulation AV-PVP-Thymol-I2 as a promising antimicrobial agent against wound infections and as a spray-on contact-killing agent.
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(This article belongs to the Section Molecular Microbiology)
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