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
Microscopic Analysis of Nuclear Speckles in a Viviparous Reptile
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
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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)
Open AccessArticle
Inactivation of Myostatin Delays Senescence via TREX1-SASP in Bovine Skeletal Muscle Cells
by
Miaomiao Yang, Li Gao, Yajie Gao, Zhenting Hao, Xinyu Zhou, Guanghua Su, Chunling Bai, Zhuying Wei, Xuefei Liu, Lei Yang and Guangpeng Li
Int. J. Mol. Sci. 2024, 25(10), 5277; https://doi.org/10.3390/ijms25105277 (registering DOI) - 12 May 2024
Abstract
The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and
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The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and age-associated muscle loss in other animals are related. In this study, we utilized MSTN gene-edited bovine skeletal muscle cells to investigate the mechanisms relating to MSTN and muscle cell senescence. The expression of MSTN was higher in older individuals than in younger individuals. We obtained consecutively passaged senescent cells and performed senescence index assays and transcriptome sequencing. We found that senescence hallmarks and the senescence-associated secretory phenotype (SASP) were decreased in long-term-cultured myostatin inactivated (MT-KO) bovine skeletal muscle cells (bSMCs). Using cell signaling profiling, MSTN was shown to regulate the SASP, predominantly through the cycle GMP-AMP synthase-stimulator of antiviral genes (cGAS-STING) pathway. An in-depth investigation by chromatin immunoprecipitation (ChIP) analysis revealed that MSTN influenced three prime repair exonuclease 1 (TREX1) expression through the SMAD2/3 complex. The downregulation of MSTN contributed to the activation of the MSTN-SMAD2/3-TREX1 signaling axis, influencing the secretion of SASP, and consequently delaying the senescence of bSMCs. This study provided valuable new insight into the role of MSTN in cell senescence in large animals.
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(This article belongs to the Section Molecular Biology)
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LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review
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Maria Eugenia Sánchez-León, Karen Julissa Loaeza-Reyes, Carlos Alberto Matias-Cervantes, Gabriel Mayoral-Andrade, Eduardo L. Pérez-Campos, Laura Pérez-Campos-Mayoral, María Teresa Hernández-Huerta, Edgar Zenteno, Yobana Pérez-Cervera and Socorro Pina-Canseco
Int. J. Mol. Sci. 2024, 25(10), 5276; https://doi.org/10.3390/ijms25105276 (registering DOI) - 12 May 2024
Abstract
LOX-1, ORL-1, or lectin-like oxidized low-density lipoprotein receptor 1 is a transmembrane glycoprotein that binds and internalizes ox-LDL in foam cells. LOX-1 is the main receptor for oxidized low-density lipoproteins (ox-LDL). The LDL comes from food intake and circulates through the bloodstream. LOX-1
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LOX-1, ORL-1, or lectin-like oxidized low-density lipoprotein receptor 1 is a transmembrane glycoprotein that binds and internalizes ox-LDL in foam cells. LOX-1 is the main receptor for oxidized low-density lipoproteins (ox-LDL). The LDL comes from food intake and circulates through the bloodstream. LOX-1 belongs to scavenger receptors (SR), which are associated with various cardiovascular diseases. The most important and severe of these is the formation of atherosclerotic plaques in the intimal layer of the endothelium. These plaques can evolve into complicated thrombi with the participation of fibroblasts, activated platelets, apoptotic muscle cells, and macrophages transformed into foam cells. This process causes changes in vascular endothelial homeostasis, leading to partial or total obstruction in the lumen of blood vessels. This obstruction can result in oxygen deprivation to the heart. Recently, LOX-1 has been involved in other pathologies, such as obesity and diabetes mellitus. However, the development of atherosclerosis has been the most relevant due to its relationship with cerebrovascular accidents and heart attacks. In this review, we will summarize findings related to the physiologic and pathophysiological processes of LOX-1 to support the detection, diagnosis, and prevention of those diseases.
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(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Open AccessArticle
Profiling of Tumor-Infiltrating Immune Cells and Their Impact on Survival in Glioblastoma Patients Undergoing Immunotherapy with Dendritic Cells
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Nataly Peres, Guilherme A. Lepski, Carla S. Fogolin, Gabriela C. M. Evangelista, Elizabeth A. Flatow, Jaqueline V. de Oliveira, Mariana P. Pinho, Patricia C. Bergami-Santos and José A. M. Barbuto
Int. J. Mol. Sci. 2024, 25(10), 5275; https://doi.org/10.3390/ijms25105275 (registering DOI) - 12 May 2024
Abstract
Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a
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Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a prospective phase II clinical trial involving allogeneic vaccination with dendritic cells (DCs). To date, six out of the thirty-seven reported cases remain alive without tumor recurrence. In this study, we focused on the characterization of infiltrating immune cells observed at the time of surgical resection. An analytical model employing a neural network-based predictive algorithm was used to ascertain the potential prognostic implications of immunological variables on patients’ overall survival. Counterintuitively, immune phenotyping of tumor-associated macrophages (TAMs) has revealed the extracellular marker PD-L1 to be a positive predictor of overall survival. In contrast, the elevated expression of CD86 within this cellular subset emerged as a negative prognostic indicator. Fundamentally, the neural network algorithm outlined here allows a prediction of the responsiveness of patients undergoing dendritic cell vaccination in terms of overall survival based on clinical parameters and the profile of infiltrated TAMs observed at the time of tumor excision.
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(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)
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Puerarin Modulates Hepatic Farnesoid X Receptor and Gut Microbiota in High-Fat Diet-Induced Obese Mice
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Ching-Wei Yang, Hsuan-Miao Liu, Zi-Yu Chang, Geng-Hao Liu, Hen-Hong Chang, Po-Yu Huang and Tzung-Yan Lee
Int. J. Mol. Sci. 2024, 25(10), 5274; https://doi.org/10.3390/ijms25105274 (registering DOI) - 12 May 2024
Abstract
Obesity is associated with alterations in lipid metabolism and gut microbiota dysbiosis. This study investigated the effects of puerarin, a bioactive isoflavone, on lipid metabolism disorders and gut microbiota in high-fat diet (HFD)-induced obese mice. Supplementation with puerarin reduced plasma alanine aminotransferase, liver
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Obesity is associated with alterations in lipid metabolism and gut microbiota dysbiosis. This study investigated the effects of puerarin, a bioactive isoflavone, on lipid metabolism disorders and gut microbiota in high-fat diet (HFD)-induced obese mice. Supplementation with puerarin reduced plasma alanine aminotransferase, liver triglyceride, liver free fatty acid (FFA), and improved gut microbiota dysbiosis in obese mice. Puerarin’s beneficial metabolic effects were attenuated when farnesoid X receptor (FXR) was antagonized, suggesting FXR-mediated mechanisms. In hepatocytes, puerarin ameliorated high FFA-induced sterol regulatory element-binding protein (SREBP) 1 signaling, inflammation, and mitochondrial dysfunction in an FXR-dependent manner. In obese mice, puerarin reduced liver damage, regulated hepatic lipogenesis, decreased inflammation, improved mitochondrial function, and modulated mitophagy and ubiquitin-proteasome pathways, but was less effective in FXR knockout mice. Puerarin upregulated hepatic expression of FXR, bile salt export pump (BSEP), and downregulated cytochrome P450 7A1 (CYP7A1) and sodium taurocholate transporter (NTCP), indicating modulation of bile acid synthesis and transport. Puerarin also restored gut microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of Clostridium celatum and Akkermansia muciniphila. This study demonstrates that puerarin effectively ameliorates metabolic disturbances and gut microbiota dysbiosis in obese mice, predominantly through FXR-dependent pathways. These findings underscore puerarin’s potential as a therapeutic agent for managing obesity and enhancing gut health, highlighting its dual role in improving metabolic functions and modulating microbial communities.
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(This article belongs to the Special Issue Gut Microbiota in Gastroenterology and Hepatology 2.0)
Open AccessArticle
Persistent Mesodermal Differentiation Capability of Bone Marrow MSCs Isolated from Aging Patients with Low-Energy Traumatic Hip Fracture and Osteoporosis: A Clinical Evidence
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Mei-Chih Wang, Wei-Lin Yu, Yun-Chiao Ding, Jun-Jae Huang, Chin-Yu Lin and Wo-Jan Tseng
Int. J. Mol. Sci. 2024, 25(10), 5273; https://doi.org/10.3390/ijms25105273 (registering DOI) - 12 May 2024
Abstract
A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures
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A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures usually suffer a higher level of bony catabolism accompanied by osteoporosis. Bone marrow-derived stem cells (BMSCs) are critical in osteogenesis, leading to metabolic homeostasis in the healthy bony microenvironment. However, whether the BMSCs derived from the patients who suffered osteoporosis and low-energy traumatic hip fractures preserve a sustained mesodermal differentiation capability, especially in osteogenesis, is yet to be explored in a clinical setting. Therefore, we aimed to collect BMSCs from clinical hip fracture patients with osteoporosis, followed by osteogenic differentiation comparison with BMSCs from healthy young donors. The CD markers identification, cytokines examination, and adipogenic differentiation were also evaluated. The data reveal that BMSCs collected from elderly osteoporotic patients secreted approximately 122.8 pg/mL interleukin 6 (IL-6) and 180.6 pg/mL vascular endothelial growth factor (VEGF), but no PDGF-BB, IL-1b, TGF-b1, IGF-1, or TNF-α secretion. The CD markers and osteogenic and adipogenic differentiation capability in BMSCs from these elderly osteoporotic patients and healthy young donors are equivalent and compliant with the standards defined by the International Society of Cell Therapy (ISCT). Collectively, our data suggest that the elderly osteoporotic patients-derived BMSCs hold equivalent differentiation and proliferation capability and intact surface markers identical to BMSCs collected from healthy youth and are available for clinical cell therapy.
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(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine (Volume 4))
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miRNA Expression Profiles In Isolated Ventricular Cardiomyocytes: Insights into Doxorubicin-Induced Cardiotoxicity
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Yohana Domínguez Romero, Gladis Montoya Ortiz, Susana Novoa Herrán, Jhon Osorio Mendez and Luis A. Gomez Grosso
Int. J. Mol. Sci. 2024, 25(10), 5272; https://doi.org/10.3390/ijms25105272 (registering DOI) - 12 May 2024
Abstract
Doxorubicin (DOX), widely used as a chemotherapeutic agent for various cancers, is limited in its clinical utility by its cardiotoxic effects. Despite its widespread use, the precise mechanisms underlying DOX-induced cardiotoxicity at the cellular and molecular levels remain unclear, hindering the development of
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Doxorubicin (DOX), widely used as a chemotherapeutic agent for various cancers, is limited in its clinical utility by its cardiotoxic effects. Despite its widespread use, the precise mechanisms underlying DOX-induced cardiotoxicity at the cellular and molecular levels remain unclear, hindering the development of preventive and early detection strategies. To characterize the cytotoxic effects of DOX on isolated ventricular cardiomyocytes, focusing on the expression of specific microRNAs (miRNAs) and their molecular targets associated with endogenous cardioprotective mechanisms such as the ATP-sensitive potassium channel (KATP), Sirtuin 1 (SIRT1), FOXO1, and GSK3β. We isolated Guinea pig ventricular cardiomyocytes by retrograde perfusion and enzymatic dissociation. We assessed cell morphology, Reactive Oxygen Species (ROS) levels, intracellular calcium, and mitochondrial membrane potential using light microscopy and specific probes. We determined the miRNA expression profile using small RNAseq and validated it using stem-loop qRT-PCR. We quantified mRNA levels of some predicted and validated molecular targets using qRT-PCR and analyzed protein expression using Western blot. Exposure to 10 µM DOX resulted in cardiomyocyte shortening, increased ROS and intracellular calcium levels, mitochondrial membrane potential depolarization, and changes in specific miRNA expression. Additionally, we observed the differential expression of KATP subunits (ABCC9, KCNJ8, and KCNJ11), FOXO1, SIRT1, and GSK3β molecules associated with endogenous cardioprotective mechanisms. Supported by miRNA gene regulatory networks and functional enrichment analysis, these findings suggest that DOX-induced cardiotoxicity disrupts biological processes associated with cardioprotective mechanisms. Further research must clarify their specific molecular changes in DOX-induced cardiac dysfunction and investigate their diagnostic biomarkers and therapeutic potential.
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(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)
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Analysis of VEGF, IGF1/2 and the Long Noncoding RNA (lncRNA) H19 Expression in Polish Women with Endometriosis
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Beata Smolarz, Tomasz Szaflik, Hanna Romanowicz, Magdalena Bryś, Ewa Forma and Krzysztof Szyłło
Int. J. Mol. Sci. 2024, 25(10), 5271; https://doi.org/10.3390/ijms25105271 (registering DOI) - 12 May 2024
Abstract
The coordinated action of VEGF, IGF1/2 and H19 factors influences the development of endometriosis. The aim of this study was to analyze the expression level of these genes in patients with endometriosis. The study group consisted of 100 patients who were diagnosed with
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The coordinated action of VEGF, IGF1/2 and H19 factors influences the development of endometriosis. The aim of this study was to analyze the expression level of these genes in patients with endometriosis. The study group consisted of 100 patients who were diagnosed with endometriosis on laparoscopic and pathological examination. The control group consisted of 100 patients who were found to be free of endometriosis during the surgical procedure and whose eutopic endometrium wasnormal on histopathological examination. These patients were operated on for uterine fibroids. Gene expression was determined by RT-PCR. The expression of the VEGF gene was significantly higher in the samples classified as clinical stage 1–2 compared to the control material (p < 0.05). There was also a statistically significant difference between the samples studied at clinical stages 1–2 and 3–4 (p < 0.01). The expression of the VEGF gene in the group classified as 1–2 was significantly higher. IGF1 gene expression was significantly lower both in the group of samples classified as clinical stages 1–2 and 3–4 compared to the control group (p < 0.05 in both cases). The expression of the H19 gene was significantly lower in the group of samples classified as clinical stage 3–4 compared to the control group (p < 0.01). The reported studies suggest significant roles of VEGF, IGF and H19 expression in the pathogenesis of endometriosis.
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(This article belongs to the Special Issue Genes and Human Diseases 2.0)
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Evolution of Caspases and the Invention of Pyroptosis
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Betsaida Bibo-Verdugo and Guy Salvesen
Int. J. Mol. Sci. 2024, 25(10), 5270; https://doi.org/10.3390/ijms25105270 (registering DOI) - 12 May 2024
Abstract
The protein scaffold that includes the caspases is ancient and found in all domains of life. However, the stringent specificity that defines the caspase biologic function is relatively recent and found only in multicellular animals. During the radiation of the Chordata, members of
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The protein scaffold that includes the caspases is ancient and found in all domains of life. However, the stringent specificity that defines the caspase biologic function is relatively recent and found only in multicellular animals. During the radiation of the Chordata, members of the caspase family adopted roles in immunity, events coinciding with the development of substrates that define the modern innate immune response. This review focuses on the switch from the non-inflammatory cellular demise of apoptosis to the highly inflammatory innate response driven by distinct members of the caspase family, and the interplay between these two regulated cell death pathways.
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(This article belongs to the Special Issue The Role of Proteases and Protease Inhibitors in the Immune System)
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Open AccessArticle
G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients
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Anna S. Zhuk, Elena I. Stepchenkova, Irina V. Zotova, Olesya B. Belopolskaya, Youri I. Pavlov, Ivan I. Kostroma, Sergey V. Gritsaev and Anna Y. Aksenova
Int. J. Mol. Sci. 2024, 25(10), 5269; https://doi.org/10.3390/ijms25105269 (registering DOI) - 12 May 2024
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes
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Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes and genotoxic drugs used to treat MM, non-canonical secondary DNA structures (four-stranded G-quadruplex structures) can affect accumulation of somatic mutations and chromosomal abnormalities in the tumor cells of MM patients. Here, we tested the hypothesis that G-quadruplex structures may influence the distribution of somatic mutations in the tumor cells of MM patients. We sequenced exomes of normal and tumor cells of 11 MM patients and analyzed the data for the presence of G4 context around points of somatic mutations. To identify molecular mechanisms that could affect mutational profile of tumors, we also analyzed mutational signatures in tumor cells as well as germline mutations for the presence of specific SNPs in DNA repair genes or in genes regulating G-quadruplex unwinding. In several patients, we found that sites of somatic mutations are frequently located in regions with G4 context. This pattern correlated with specific germline variants found in these patients. We discuss the possible implications of these variants for mutation accumulation and specificity in MM and propose that the extent of G4 context enrichment around somatic mutation sites may be a novel metric characterizing mutational processes in tumors.
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(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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Crucial Involvement of Heme Biosynthesis in Vegetative Growth, Development, Stress Response, and Fungicide Sensitivity of Fusarium graminearum
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Jin Wang, Yingying Cao, Dongya Shi, Zhihui Zhang, Xin Li and Changjun Chen
Int. J. Mol. Sci. 2024, 25(10), 5268; https://doi.org/10.3390/ijms25105268 (registering DOI) - 12 May 2024
Abstract
Heme biosynthesis is a highly conserved pathway from bacteria to higher animals. Heme, which serves as a prosthetic group for various enzymes involved in multiple biochemical processes, is essential in almost all species, making heme homeostasis vital for life. However, studies on the
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Heme biosynthesis is a highly conserved pathway from bacteria to higher animals. Heme, which serves as a prosthetic group for various enzymes involved in multiple biochemical processes, is essential in almost all species, making heme homeostasis vital for life. However, studies on the biological functions of heme in filamentous fungi are scarce. In this study, we investigated the role of heme in Fusarium graminearum. A mutant lacking the rate-limiting enzymes in heme synthesis, coproporphyrinogen III oxidase (Cpo) or ferrochelatase (Fc), was constructed using a homologous recombination strategy. The results showed that the absence of these enzymes was lethal to F. graminearum, but the growth defect could be rescued by the addition of hemin, so we carried out further studies with the help of hemin. The results demonstrated that heme was required for the activity of FgCyp51, and its absence increased the sensitivity to tebuconazole and led to the upregulation of FgCYP51 in F. graminearum. Additionally, heme plays an indispensable role in the life cycle of F. graminearum, which is essential for vegetative growth, conidiation, external stress response (especially oxidative stress), lipid accumulation, fatty acid β-oxidation, autophagy, and virulence.
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(This article belongs to the Section Molecular Biology)
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DDCM: A Computational Strategy for Drug Repositioning Based on Support-Vector Regression Algorithm
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Manyi Xu, Wan Li, Jiaheng He, Yahui Wang, Junjie Lv, Weiming He, Lina Chen and Hui Zhi
Int. J. Mol. Sci. 2024, 25(10), 5267; https://doi.org/10.3390/ijms25105267 (registering DOI) - 12 May 2024
Abstract
Computational drug-repositioning technology is an effective tool for speeding up drug development. As biological data resources continue to grow, it becomes more important to find effective methods to identify potential therapeutic drugs for diseases. The effective use of valuable data has become a
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Computational drug-repositioning technology is an effective tool for speeding up drug development. As biological data resources continue to grow, it becomes more important to find effective methods to identify potential therapeutic drugs for diseases. The effective use of valuable data has become a more rational and efficient approach to drug repositioning. The disease–drug correlation method (DDCM) proposed in this study is a novel approach that integrates data from multiple sources and different levels to predict potential treatments for diseases, utilizing support-vector regression (SVR). The DDCM approach resulted in potential therapeutic drugs for neoplasms and cardiovascular diseases by constructing a correlation hybrid matrix containing the respective similarities of drugs and diseases, implementing the SVR algorithm to predict the correlation scores, and undergoing a randomized perturbation and stepwise screening pipeline. Some potential therapeutic drugs were predicted by this approach. The potential therapeutic ability of these drugs has been well-validated in terms of the literature, function, drug target, and survival-essential genes. The method’s feasibility was confirmed by comparing the predicted results with the classical method and conducting a co-drug analysis of the sub-branch. Our method challenges the conventional approach to studying disease–drug correlations and presents a fresh perspective for understanding the pathogenesis of diseases.
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(This article belongs to the Section Molecular Informatics)
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Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat
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Youngnam Kang, Mitsuru Saito and Hiroki Toyoda
Int. J. Mol. Sci. 2024, 25(10), 5266; https://doi.org/10.3390/ijms25105266 (registering DOI) - 12 May 2024
Abstract
The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of
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The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control.
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(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)
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Evaluation of New Approaches to Depression Treatment Using an Animal Model of Phramacoresistant Depression
by
Alexandra Zvozilova, Stanislava Bukatova, Romana Koprdova and Mojmir Mach
Int. J. Mol. Sci. 2024, 25(10), 5265; https://doi.org/10.3390/ijms25105265 (registering DOI) - 12 May 2024
Abstract
Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic
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Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.
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(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)
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N-Terminal Amino Acid Affects the Translation Efficiency at Lower Temperatures in a Reconstituted Protein Synthesis System
by
Tomoe Fuse-Murakami, Rena Matsumoto and Takashi Kanamori
Int. J. Mol. Sci. 2024, 25(10), 5264; https://doi.org/10.3390/ijms25105264 (registering DOI) - 12 May 2024
Abstract
The Escherichia coli (E. coli)-based protein synthesis using recombinant elements (PURE) system is a cell-free protein synthesis system reconstituted from purified factors essential for E. coli translation. The PURE system is widely used for basic and synthetic biology applications. One of
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The Escherichia coli (E. coli)-based protein synthesis using recombinant elements (PURE) system is a cell-free protein synthesis system reconstituted from purified factors essential for E. coli translation. The PURE system is widely used for basic and synthetic biology applications. One of the major challenges associated with the PURE system is that the protein yield of the system varies depending on the protein. Studies have reported that the efficiency of translation is significantly affected by nucleotide and amino acid sequences, especially in the N-terminal region. Here, we investigated the inherent effect of various N-terminal sequences on protein synthesis using the PURE system. We found that a single amino acid substitution in the N-terminal region significantly altered translation efficiency in the PURE system, especially at low temperatures. This result gives us useful suggestions for the expression of the protein of interest in vitro and in vivo.
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(This article belongs to the Special Issue Versatility of Protein Synthesis in a Test Tube)
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Cartilage Oligomeric Matrix Protein in Osteoarthritis and Obesity—Do New Considerations Emerge?
by
Sevdalina Nikolova Lambova, Tsvetelina Batsalova, Dzhemal Moten and Balik Dzhambazov
Int. J. Mol. Sci. 2024, 25(10), 5263; https://doi.org/10.3390/ijms25105263 (registering DOI) - 12 May 2024
Abstract
The diagnosis of osteoarthritis (OA) is based on radiological changes that are delayed, along with clinical symptoms. Early and very early diagnosis at the stage of molecular pathology may eventually offer an opportunity for early therapeutic intervention that may retard and prevent future
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The diagnosis of osteoarthritis (OA) is based on radiological changes that are delayed, along with clinical symptoms. Early and very early diagnosis at the stage of molecular pathology may eventually offer an opportunity for early therapeutic intervention that may retard and prevent future damage. Cartilage oligomeric matrix protein (COMP) is a non-collagenous extracellular matrix protein that promotes the secretion and aggregation of collagen and contributes to the stability of the extracellular matrix. There are contradictory literature data and currently, the parameter is used only for scientific purposes and its significance is not well-determined. The serum level of COMP in patients with metabolic type OA of the knee has not been evaluated. The aim of the study was to analyze serum COMP levels in metabolic knee OA and controls with different BMI. Our results showed that the mean COMP values were significantly higher in the control group (1518.69 ± 232.76 ng/mL) compared to the knee OA patients (1294.58 ± 360.77 ng/mL) (p = 0.0012). This may be related to the smaller cartilage volume in OA patients. Additionally, COMP levels negatively correlated with disease duration (p = 0.04). The COMP level in knee OA with BMI below 30 kg/m2 (n = 61, 1304.50 ± 350.60 ng/mL) was higher compared to cases with BMI ≥ 30 kg/m2 (n = 76, 1286.63 ± 370.86 ng/mL), but the difference was not significant (p = 0.68). Whether this finding is related to specific features in the evolution of the metabolic type of knee OA remains to be determined. Interestingly, comparison of COMP levels in the controls with different BMI revealed significantly higher values in overweight and obese individuals (1618.36 ± 203.76 ng/mL in controls with BMI ≥ 25 kg/m2, n = 18, 1406.61 ± 216.41 ng/mL, n = 16; p = 0.0092). Whether this finding is associated with increased expression of COMP in the adipose tissue or with more intensive cartilage metabolism in relation to higher biomechanical overload in obese patients, considering the earlier development of metabolic type knee OA as an isolated finding, remains to be determined.
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(This article belongs to the Special Issue Molecular Advances in Bone Metabolism and Disorders)
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Physiological and Proteomic Responses of the Tetraploid Robinia pseudoacacia L. to High CO2 Levels
by
Jianxin Li, Subin Zhang, Pei Lei, Liyong Guo, Xiyang Zhao and Fanjuan Meng
Int. J. Mol. Sci. 2024, 25(10), 5262; https://doi.org/10.3390/ijms25105262 (registering DOI) - 11 May 2024
Abstract
The increase in atmospheric CO2 concentration is a significant factor in triggering global warming. CO2 is essential for plant photosynthesis, but excessive CO2 can negatively impact photosynthesis and its associated physiological and biochemical processes. The tetraploid Robinia pseudoacacia L., a
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The increase in atmospheric CO2 concentration is a significant factor in triggering global warming. CO2 is essential for plant photosynthesis, but excessive CO2 can negatively impact photosynthesis and its associated physiological and biochemical processes. The tetraploid Robinia pseudoacacia L., a superior and improved variety, exhibits high tolerance to abiotic stress. In this study, we investigated the physiological and proteomic response mechanisms of the tetraploid R. pseudoacacia under high CO2 treatment. The results of our physiological and biochemical analyses revealed that a 5% high concentration of CO2 hindered the growth and development of the tetraploid R. pseudoacacia and caused severe damage to the leaves. Additionally, it significantly reduced photosynthetic parameters such as Pn, Gs, Tr, and Ci, as well as respiration. The levels of chlorophyll (Chl a and b) and the fluorescent parameters of chlorophyll (Fm, Fv/Fm, qP, and ETR) also significantly decreased. Conversely, the levels of ROS (H2O2 and O2·−) were significantly increased, while the activities of antioxidant enzymes (SOD, CAT, GR, and APX) were significantly decreased. Furthermore, high CO2 induced stomatal closure by promoting the accumulation of ROS and NO in guard cells. Through a proteomic analysis, we identified a total of 1652 DAPs after high CO2 treatment. GO functional annotation revealed that these DAPs were mainly associated with redox activity, catalytic activity, and ion binding. KEGG analysis showed an enrichment of DAPs in metabolic pathways, secondary metabolite biosynthesis, amino acid biosynthesis, and photosynthetic pathways. Overall, our study provides valuable insights into the adaptation mechanisms of the tetraploid R. pseudoacacia to high CO2.
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(This article belongs to the Special Issue Molecular Advance in Abiotic Stress Signaling in Plants: Focus on Atmospheric Stressors)
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