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 15.9 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the second half of 2022).
- 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:
6.208 (2021);
5-Year Impact Factor:
6.628 (2021)
Latest Articles
Amh/Amhr2 Signaling Causes Masculinization by Inhibiting Estrogen Synthesis during Gonadal Sex Differentiation in Japanese Flounder (Paralichthys olivaceus)
Int. J. Mol. Sci. 2023, 24(3), 2480; https://doi.org/10.3390/ijms24032480 (registering DOI) - 27 Jan 2023
Abstract
The anti-Müllerian hormone (Amh) is a protein belonging to the TGF-β superfamily, the function of which has been considered important for male sex differentiation in vertebrates. The Japanese flounder (Paralichthys olivaceus) is a teleost fish that has an XX/XY sex determination
[...] Read more.
The anti-Müllerian hormone (Amh) is a protein belonging to the TGF-β superfamily, the function of which has been considered important for male sex differentiation in vertebrates. The Japanese flounder (Paralichthys olivaceus) is a teleost fish that has an XX/XY sex determination system and temperature-dependent sex determination. In this species, amh expression is up-regulated in genetic males and in temperature-induced masculinization during the sex differentiation period. However, to the best of our knowledge, no reports on the Amh receptor (Amhr2) in flounder have been published, and the details of Amh signaling remain unclear. In this study, we produced amhr2-deficient mutants using the CRISPR/Cas9 system and analyzed the gonadal phenotypes and sex-related genes. The results revealed that the gonads of genetically male amhr2 mutants featured typical ovaries, and the sex differentiation-related genes showed a female expression pattern. Thus, the loss of Amhr2 function causes male-to-female sex reversal in Japanese flounder. Moreover, the treatment of genetically male amhr2 mutants with an aromatase inhibitor fadrozole, which inhibits estrogen synthesis, resulted in testicular formation. These results strongly suggest that Amh/Amhr2 signaling causes masculinization by inhibiting estrogen synthesis during gonadal sex differentiation in the flounder.
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(This article belongs to the Special Issue Sex Hormones and Sex Differentiation)
Open AccessReview
The Journey of Mitochondrial Protein Import and the Roadmap to Follow
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, , , and
Int. J. Mol. Sci. 2023, 24(3), 2479; https://doi.org/10.3390/ijms24032479 (registering DOI) - 27 Jan 2023
Abstract
Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the
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Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.
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(This article belongs to the Special Issue Mitochondria in Human Diseases)
Open AccessArticle
Serum Amyloid A in Stable Patients with Chronic Obstructive Pulmonary Disease Does Not Reflect the Clinical Course of the Disease
by
, , , , , and
Int. J. Mol. Sci. 2023, 24(3), 2478; https://doi.org/10.3390/ijms24032478 (registering DOI) - 27 Jan 2023
Abstract
Serum amyloid A (SAA) is a good systemic marker of the exacerbations of chronic obstructive pulmonary disease (COPD), but the significance of SAA in stable patients with COPD has not been widely investigated. We aimed to evaluate the SAA level in peripheral blood
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Serum amyloid A (SAA) is a good systemic marker of the exacerbations of chronic obstructive pulmonary disease (COPD), but the significance of SAA in stable patients with COPD has not been widely investigated. We aimed to evaluate the SAA level in peripheral blood from stable patients with COPD and to search for correlations between SAA and other inflammatory markers and clinical characteristics of the disease. Serum SAA, IL-6, IL-8, TNF-alpha, basic blood investigations, pulmonary function testing and a 6-min walk test were performed. The correlations between SAA and other inflammatory markers, functional performance and the number of disease exacerbations were evaluated. A total of 100 consecutive patients with COPD were analyzed. No correlations between SAA and inflammatory markers as well as pulmonary function were found. Hierarchical clustering identified two clusters incorporating SAA: one comprised SAA, PaO2 and FEV1 and the second was formed of SAA and nine other disease markers. The SAA level was higher in patients with blood eosinophils < 2% when compared to those with blood eosinophils ≥ 2% (41.8 (19.5–69.7) ng/mL vs. 18.9 (1.0–54.5) ng/mL, respectively, p = 0.04). We conclude that, in combination with other important disease features, SAA may be useful for patient evaluation in stable COPD.
Full article
(This article belongs to the Special Issue Immunogenic Cell Death, Immunogenic Surrender and Antitumor Immunity)
Open AccessReview
The Interplay between α-Synuclein and Microglia in α-Synucleinopathies
Int. J. Mol. Sci. 2023, 24(3), 2477; https://doi.org/10.3390/ijms24032477 (registering DOI) - 27 Jan 2023
Abstract
Synucleinopathies are a set of devastating neurodegenerative diseases that share a pathologic accumulation of the protein α-synuclein (α-syn). This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown,
[...] Read more.
Synucleinopathies are a set of devastating neurodegenerative diseases that share a pathologic accumulation of the protein α-synuclein (α-syn). This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown, microglia, the resident immune cells of the central nervous system (CNS), have been consistently implicated in the pathogenesis of synucleinopathies. Microglia are generally believed to be neuroprotective in the early stages of α-syn accumulation and contribute to further neurodegeneration in chronic disease states. While the molecular mechanisms by which microglia achieve this role are still being investigated, here we highlight the major findings to date. In this review, we describe how structural varieties of inherently disordered α-syn result in varied microglial receptor-mediated interactions. We also summarize which microglial receptors enable cellular recognition and uptake of α-syn. Lastly, we review the downstream effects of α-syn processing within microglia, including spread to other brain regions resulting in neuroinflammation and neurodegeneration in chronic disease states. Understanding the mechanism of microglial interactions with α-syn is vital to conceptualizing molecular targets for novel therapeutic interventions. In addition, given the significant diversity in the pathophysiology of synucleinopathies, such molecular interactions are vital in gauging all potential pathways of neurodegeneration in the disease state.
Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia)
Open AccessCommunication
Influence of Perinatal Factors on Gene Expression of IAPs Family and Main Factors of Pluripotency: OCT4 and SOX2 in Human Breast Milk Stem Cells—A Preliminary Report
by
,
Michał Leśniewski
, , , , , , , , , , , , , , , , and
Int. J. Mol. Sci. 2023, 24(3), 2476; https://doi.org/10.3390/ijms24032476 (registering DOI) - 27 Jan 2023
Abstract
Due to their therapeutic potential, mesenchymal stem cells are the subject of intensive research on the use of their potential in the treatment of, among others, neurodegenerative diseases or immunological diseases. They are among the newest in the field of medicine. The presented
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Due to their therapeutic potential, mesenchymal stem cells are the subject of intensive research on the use of their potential in the treatment of, among others, neurodegenerative diseases or immunological diseases. They are among the newest in the field of medicine. The presented study aimed to evaluate the expression of eight genes from the IAP family and the gene regulating IAP—XAF1—in stem cells derived from human milk, using the qPCR method. The relationships between the expression of genes under study and clinical data, such as maternal age, maternal BMI, week of pregnancy in which the delivery took place, bodyweight of the newborn, the number of pregnancies and deliveries, and the time elapsed since delivery, were also analyzed. The research was carried out on samples of human milk collected from 42 patients hospitalized in The Clinic of Obstetrics and Perinatology of the Independent Public Clinical Hospital No. 4, in Lublin. The conducted research confirmed the expression of the following genes in the tested material: NAIP, BIRC2, BIRC3, BIRC5, BIRC6, BIRC8, XIAP, XAF1, OCT4 and SOX2. Moreover, several dependencies of the expression of individual genes on the maternal BMI (BIRC5, XAF1 and NAIP), the time since childbirth (BIRC5, BIRC6, XAF1 and NAIP), the number of pregnancies and deliveries (BIRC2, BIRC5, BIRC6 and XAF1), the manner of delivery (XAF1 and OCT4), preterm labor (BIRC6 and NAIP) were demonstrated. Additionally, we found positive relationships between gene expression of BIRC7, BIRC8 and XAF1 and the main factors of pluripotency: SOX2 and OCT4. This work is the first to investigate the expression of genes from the IAPs family in mother’s milk stem cells.
Full article
(This article belongs to the Special Issue From Cell to Organism: Cytological, Experimental Molecular and Medical Aspects)
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Open AccessArticle
Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish
by
, , , and
Int. J. Mol. Sci. 2023, 24(3), 2475; https://doi.org/10.3390/ijms24032475 (registering DOI) - 27 Jan 2023
Abstract
Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER)
[...] Read more.
Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) of hepatocytes. Transgenic zebrafish expressing human ZAAT show no signs of hepatic accumulation despite displaying serum insufficiency, suggesting the defect in ZAAT secretion occurs independently of its tendency to form inclusion bodies. In this study, proteomic, transcriptomic, and biochemical analysis provided evidence of suppressed Srebp2-mediated cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish. To investigate the basis for this perturbation, CRISPR/Cas9 gene editing was used to manipulate ER protein quality control factors. Mutation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD). Mutation of the two ER mannosidase homologs enhanced ZAAT secretion without inducing hepatic accumulation. These insights into hepatic ZAAT processing suggest potential therapeutic targets to improve secretion and alleviate serum insufficiency in this form of the α1-antitrypsin disease.
Full article
(This article belongs to the Special Issue Zebrafish as a Model in Human Disease)
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Open AccessArticle
The Comprehensive Steroidome in Complete TSPO/PBR Knockout Mice under Basal Conditions
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, , , , and
Int. J. Mol. Sci. 2023, 24(3), 2474; https://doi.org/10.3390/ijms24032474 (registering DOI) - 27 Jan 2023
Abstract
The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR
[...] Read more.
The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR has remained controversial. The aim of this study was to provide insight into the steroid profile in complete C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout male mice (TSPO-KO) under basal conditions. The steroidome in the brain, adrenal glands, testes and plasma was measured by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). We found that steroids present in wild-type (WT) mice were also detected in TSPO-KO mice, including pregnenolone (PREG), progestogens, mineralo-glucocorticosteroids and androgens. The concentrations of PREG and most metabolites were similar between genotypes, except a significant decrease in the levels of the 5α-reduced metabolites of progesterone (PROG) in adrenal glands and plasma and of the 5α-reduced metabolites of corticosterone (B) in plasma in TSPO-KO compared to WT animals, suggesting other regulatory functions for the TSPO/PBR. The expression levels of the voltage-dependent anion-selective channel (VDAC-1), CYP11A1 and 5α-reductase were not significantly different between both groups. Thus, the complete deletion of the tspo gene in male mice does not impair de novo steroidogenesis in vivo.
Full article
(This article belongs to the Collection 21st Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)
Open AccessArticle
Mechanical Properties of Twisted Carbon Nanotube Bundles with Carbon Linkers from Molecular Dynamics Simulations
Int. J. Mol. Sci. 2023, 24(3), 2473; https://doi.org/10.3390/ijms24032473 (registering DOI) - 27 Jan 2023
Abstract
The manufacturing of high-modulus, high-strength fibers is of paramount importance for real-world, high-end applications. In this respect, carbon nanotubes represent the ideal candidates for realizing such fibers. However, their remarkable mechanical performance is difficult to bring up to the macroscale, due to the
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The manufacturing of high-modulus, high-strength fibers is of paramount importance for real-world, high-end applications. In this respect, carbon nanotubes represent the ideal candidates for realizing such fibers. However, their remarkable mechanical performance is difficult to bring up to the macroscale, due to the low load transfer within the fiber. A strategy to increase such load transfer is the introduction of chemical linkers connecting the units, which can be obtained, for example, using carbon ion-beam irradiation. In this work, we investigate, via molecular dynamics simulations, the mechanical properties of twisted nanotube bundles in which the linkers are composed of interstitial single carbon atoms. We find a significant interplay between the twist and the percentage of linkers. Finally, we evaluate the suitability of two different force fields for the description of these systems: the dihedral-angle-corrected registry-dependent potential, which we couple for non-bonded interaction with either the AIREBO potential or the screened potential ReboScr2. We show that both of these potentials show some shortcomings in the investigation of the mechanical properties of bundles with carbon linkers.
Full article
(This article belongs to the Collection Feature Papers in Materials Science)
Open AccessArticle
A Comprehensive Investigation of Genomic Variants in Prostate Cancer Reveals 30 Putative Regulatory Variants
Int. J. Mol. Sci. 2023, 24(3), 2472; https://doi.org/10.3390/ijms24032472 (registering DOI) - 27 Jan 2023
Abstract
Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in the world. Previous studies have shown that genomic alterations represent the most common mechanism for molecular alterations responsible for the development and progression of PC. This highlights the importance of identifying functional
[...] Read more.
Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in the world. Previous studies have shown that genomic alterations represent the most common mechanism for molecular alterations responsible for the development and progression of PC. This highlights the importance of identifying functional genomic variants for early detection in high-risk PC individuals. Great efforts have been made to identify common protein-coding genetic variations; however, the impact of non-coding variations, including regulatory genetic variants, is not well understood. Identification of these variants and the underlying target genes will be a key step in improving the detection and treatment of PC. To gain an understanding of the functional impact of genetic variants, and in particular, regulatory variants in PC, we developed an integrative pipeline (AGV) that uses whole genome/exome sequences, GWAS SNPs, chromosome conformation capture data, and ChIP-Seq signals to investigate the potential impact of genomic variants on the underlying target genes in PC. We identified 646 putative regulatory variants, of which 30 significantly altered the expression of at least one protein-coding gene. Our analysis of chromatin interactions data (Hi-C) revealed that the 30 putative regulatory variants could affect 131 coding and non-coding genes. Interestingly, our study identified the 131 protein-coding genes that are involved in disease-related pathways, including Reactome and MSigDB, for most of which targeted treatment options are currently available. Notably, our analysis revealed several non-coding RNAs, including RP11-136K7.2 and RAMP2-AS1, as potential enhancer elements of the protein-coding genes CDH12 and EZH1, respectively. Our results provide a comprehensive map of genomic variants in PC and reveal their potential contribution to prostate cancer progression and development.
Full article
(This article belongs to the Special Issue Bioinformatics in Genetic Diseases and Cancer)
Open AccessReview
Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites
by
, , , , and
Int. J. Mol. Sci. 2023, 24(3), 2471; https://doi.org/10.3390/ijms24032471 (registering DOI) - 27 Jan 2023
Abstract
Necrotizing enterocolitis (NEC) is a life-threatening disease that predominantly affects very low birth weight preterm infants. Development of NEC in preterm infants is accompanied by high mortality. Surgical treatment of NEC can be complicated by short bowel syndrome, intestinal failure, parenteral nutrition-associated liver
[...] Read more.
Necrotizing enterocolitis (NEC) is a life-threatening disease that predominantly affects very low birth weight preterm infants. Development of NEC in preterm infants is accompanied by high mortality. Surgical treatment of NEC can be complicated by short bowel syndrome, intestinal failure, parenteral nutrition-associated liver disease, and neurodevelopmental delay. Issues surrounding pathogenesis, prevention, and treatment of NEC remain unclear. This review summarizes data on prenatal risk factors for NEC, the role of pre-eclampsia, and intrauterine growth retardation in the pathogenesis of NEC. The role of hypoxia in NEC is discussed. Recent data on the role of the intestinal microbiome in the development of NEC, and features of the metabolome that can serve as potential biomarkers, are presented. The Pseudomonadota phylum is known to be associated with NEC in preterm neonates, and the role of other bacteria and their metabolites in NEC pathogenesis is also discussed. The most promising approaches for preventing and treating NEC are summarized.
Full article
(This article belongs to the Special Issue Microbiome and Metabolome in the Gastrointestinal Tract)
Open AccessArticle
Genetic Diversity and Population Structure of a Wide Pisum spp. Core Collection
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, , , and
Int. J. Mol. Sci. 2023, 24(3), 2470; https://doi.org/10.3390/ijms24032470 (registering DOI) - 27 Jan 2023
Abstract
Peas (Pisum sativum) are the fourth most cultivated pulses worldwide and a critical source of protein in animal feed and human food. Developing pea core collections improves our understanding of pea evolution and may ease the exploitation of their genetic diversity
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Peas (Pisum sativum) are the fourth most cultivated pulses worldwide and a critical source of protein in animal feed and human food. Developing pea core collections improves our understanding of pea evolution and may ease the exploitation of their genetic diversity in breeding programs. We carefully selected a highly diverse pea core collection of 325 accessions and established their genetic diversity and population structure. DArTSeq genotyping provided 35,790 polymorphic DArTseq markers, of which 24,279 were SilicoDArT and 11,511 SNP markers. More than 90% of these markers mapped onto the pea reference genome, with an average of 2787 SilicoDArT and 1644 SNP markers per chromosome, and an average LD50 distance of 0.48 and 1.38 Mbp, respectively. The pea core collection clustered in three or six subpopulations depending on the pea subspecies. Many admixed accessions were also detected, confirming the frequent genetic exchange between populations. Our results support the classification of Pisum genus into two species, P. fulvum and P. sativum (including subsp. sativum, arvense, elatius, humile, jomardii and abyssinicum). In addition, the study showed that wild alleles were incorporated into the cultivated pea through the intermediate P. sativum subsp. jomardii and P. sativum subsp. arvense during pea domestication, which have important implications for breeding programs. The high genetic diversity found in the collection and the high marker coverage are also expected to improve trait discovery and the efficient implementation of advanced breeding approaches.
Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of 200th Anniversary of the Birth of Gregor Johann Mendel: The Genius of Genetics)
Open AccessArticle
Elevated Expression of ADAM10 in Skeletal Muscle of Patients with Idiopathic Inflammatory Myopathies Could Be Responsible for FNDC5/Irisin Unbalance
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, , , , , , , , and
Int. J. Mol. Sci. 2023, 24(3), 2469; https://doi.org/10.3390/ijms24032469 (registering DOI) - 27 Jan 2023
Abstract
Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory
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Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory infiltrates. Muscle biopsies and laboratory tests are helpful in diagnosis, but currently, few biomarkers of disease activity and progression are available. In this context, we conducted a cohort study of forty-one DM and IMNM patients, aged 40–70 years. In comparison with control subjects, in the muscle biopsies of these patients, there was a lower expression of FNDC5, the precursor of irisin, a myokine playing a key role in musculoskeletal metabolism. Expectedly, the muscle cross-sectional areas of these patients were reduced, while, surprisingly, serum irisin levels were higher than in CTRL, as were mRNA levels of ADAM10, a metalloproteinase recently shown to be the cleavage agent for FNDC5. We hypothesize that elevated expression of ADAM10 in the skeletal muscle of DM and IMNM patients might be responsible for the discrepancy between irisin levels and FNDC5 expression. Future studies will be needed to understand the mechanisms underlying exacerbated FNDC5 cleavage and muscle irisin resistance in these inflammatory myopathies.
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(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)
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Open AccessReview
Master-Key Regulators of Sex Determination in Fish and Other Vertebrates—A Review
Int. J. Mol. Sci. 2023, 24(3), 2468; https://doi.org/10.3390/ijms24032468 (registering DOI) - 27 Jan 2023
Abstract
In vertebrates, mainly single genes with an allele ratio of 1:1 trigger sex-determination (SD), leading to initial equal sex-ratios. Such genes are designated master-key regulators (MKRs) and are frequently associated with DNA structural variations, such as copy-number variation and null-alleles. Most MKR knowledge
[...] Read more.
In vertebrates, mainly single genes with an allele ratio of 1:1 trigger sex-determination (SD), leading to initial equal sex-ratios. Such genes are designated master-key regulators (MKRs) and are frequently associated with DNA structural variations, such as copy-number variation and null-alleles. Most MKR knowledge comes from fish, especially cichlids, which serve as a genetic model for SD. We list 14 MKRs, of which dmrt1 has been identified in taxonomically distant species such as birds and fish. The identification of MKRs with known involvement in SD, such as amh and fshr, indicates that a common network drives SD. We illustrate a network that affects estrogen/androgen equilibrium, suggesting that structural variation may exert over-expression of the gene and thus form an MKR. However, the reason why certain factors constitute MKRs, whereas others do not is unclear. The limited number of conserved MKRs suggests that their heterologous sequences could be used as targets in future searches for MKRs of additional species. Sex-specific mortality, sex reversal, the role of temperature in SD, and multigenic SD are examined, claiming that these phenomena are often consequences of artificial hybridization. We discuss the essentiality of taxonomic authentication of species to validate purebred origin before MKR searches.
Full article
(This article belongs to the Special Issue Sex Determination Mechanisms and Disease 2.0)
Open AccessArticle
Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma
Int. J. Mol. Sci. 2023, 24(3), 2467; https://doi.org/10.3390/ijms24032467 (registering DOI) - 27 Jan 2023
Abstract
Alterations of sphingolipids and their metabolizing enzymes play a role in various diseases. However, peripheral biomarkers for such changes are limited. Particularly, in the increasingly reported involvement of neutral sphingomyelinase (NSM) with four described isoforms in tissues or cells, a peripheral marker is
[...] Read more.
Alterations of sphingolipids and their metabolizing enzymes play a role in various diseases. However, peripheral biomarkers for such changes are limited. Particularly, in the increasingly reported involvement of neutral sphingomyelinase (NSM) with four described isoforms in tissues or cells, a peripheral marker is lacking. We here describe the detection of an NSM activity in human serum and plasma samples which hydrolyses fluorescently labeled sphingomyelin to ceramide in a time- and volume-dependent manner. Reaction rates were linear up to 10 days, and serum volumes above 2 vol-% were inhibitory. Biochemical properties were different from acid sphingomyelinase (ASM) with respect to detergent specificity (sodium deoxycholate), pH profile (pH 7–9), and cation dependence: Serum NSM activity was inhibited by EDTA ≥ 1 µM and restored in EDTA-anticoagulated plasma with the addition of ≥ 100 µM Co2+. It was independent of Mg2+, the typical cofactor of cellular NSM species, and even inhibited by [Mg2+] ≥ 20 mM. Serum NSM activity was not correlated with ASM activity and was independent of sex and age in 24 healthy adults. Since human peripheral NSM activity is very low and activities in rodents are even lower or undetectable, future research should aim to increase the reaction rate and determine the source of this enzymatic activity. The established activity could serve as a future biomarker or therapeutic target in diseases affected by sphingolipid derangements.
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(This article belongs to the Special Issue State-of-the-Art Biochemistry in Germany)
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Open AccessArticle
Identification of Alternative Splicing in Proteomes of Human Melanoma Cell Lines without RNA Sequencing Data
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, , , , , , and
Int. J. Mol. Sci. 2023, 24(3), 2466; https://doi.org/10.3390/ijms24032466 (registering DOI) - 27 Jan 2023
Abstract
Alternative splicing is one of the main regulation pathways in living cells beyond simple changes in the level of protein expression. Most of the approaches proposed in proteomics for the identification of specific splicing isoforms require a preliminary deep transcriptomic analysis of the
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Alternative splicing is one of the main regulation pathways in living cells beyond simple changes in the level of protein expression. Most of the approaches proposed in proteomics for the identification of specific splicing isoforms require a preliminary deep transcriptomic analysis of the sample under study, which is not always available, especially in the case of the re-analysis of previously acquired data. Herein, we developed new algorithms for the identification and validation of protein splice isoforms in proteomic data in the absence of RNA sequencing of the samples under study. The bioinformatic approaches were tested on the results of proteome analysis of human melanoma cell lines, obtained earlier by high-resolution liquid chromatography and mass spectrometry (LC-MS). A search for alternative splicing events for each of the cell lines studied was performed against the database generated from all known transcripts (RefSeq) and the one composed of peptide sequences, which included all biologically possible combinations of exons. The identifications were filtered using the prediction of both retention times and relative intensities of fragment ions in the corresponding mass spectra. The fragmentation mass spectra corresponding to the discovered alternative splicing events were additionally examined for artifacts. Selected splicing events were further validated at the mRNA level by quantitative PCR.
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(This article belongs to the Special Issue Molecular Research Using Omics Technologies for Human Health)
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Open AccessCommunication
SABRE Hyperpolarization with up to 200 bar Parahydrogen in Standard and Quickly Removable Solvents
Int. J. Mol. Sci. 2023, 24(3), 2465; https://doi.org/10.3390/ijms24032465 (registering DOI) - 27 Jan 2023
Abstract
Parahydrogen (p-H2)-based techniques are known to drastically enhance NMR signals but are usually limited by p-H2 supply. This work reports p-H2-based SABRE hyperpolarization at p-H2 pressures of hundreds of bar, far
[...] Read more.
Parahydrogen (p-H2)-based techniques are known to drastically enhance NMR signals but are usually limited by p-H2 supply. This work reports p-H2-based SABRE hyperpolarization at p-H2 pressures of hundreds of bar, far beyond the typical ten bar currently reported in the literature. A recently designed high-pressure setup was utilized to compress p-H2 gas up to 200 bar. The measurements were conducted using a sapphire high-pressure NMR tube and a 43 MHz benchtop NMR spectrometer. In standard methanol solutions, it could be shown that the signal intensities increased with pressure until they eventually reached a plateau. A polarization of about 2%, equal to a molar polarization of 1.2 mmol L−1, could be achieved for the sample with the highest substrate concentration. While the signal plateaued, the H2 solubility increased linearly with pressure from 1 to 200 bar, indicating that p-H2 availability is not the limiting factor in signal enhancement beyond a certain pressure, depending on sample composition. Furthermore, the possibility of using liquefied ethane and compressed CO2 as removable solvents for hyperpolarization was demonstrated. The use of high pressures together with quickly removable organic/non-organic solvents represents an important breakthrough in the field of hyperpolarization, advancing SABRE as a promising tool for materials science, biophysics, and molecular imaging.
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(This article belongs to the Special Issue Modern NMR Characterization of Materials)
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Open AccessArticle
Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-Like 1 Peptide Action in White Adipose Tissue
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, , , , , , , , and
Int. J. Mol. Sci. 2023, 24(3), 2464; https://doi.org/10.3390/ijms24032464 (registering DOI) - 27 Jan 2023
Abstract
Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional
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Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.
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(This article belongs to the Special Issue Molecular Pharmacology in Diabetes)
Open AccessArticle
SAV-Pred: A Freely Available Web Application for the Prediction of Pathogenic Amino Acid Substitutions for Monogenic Hereditary Diseases Studied in Newborn Screening
Int. J. Mol. Sci. 2023, 24(3), 2463; https://doi.org/10.3390/ijms24032463 - 27 Jan 2023
Abstract
Next Generation Sequencing (NGS) technologies are rapidly entering clinical practice. A promising area for their use lies in the field of newborn screening. The mass screening of newborns using NGS technology leads to the discovery of a large number of new missense variants
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Next Generation Sequencing (NGS) technologies are rapidly entering clinical practice. A promising area for their use lies in the field of newborn screening. The mass screening of newborns using NGS technology leads to the discovery of a large number of new missense variants that need to be assessed for association with the development of hereditary diseases. Currently, the primary analysis and identification of pathogenic variations is carried out using bioinformatic tools. Although extensive efforts have been made in the computational approach to variant interpretation, there is currently no generally accepted pathogenicity predictor. In this study, we used the sequence–structure–property relationships (SSPR) approach, based on the representation of protein fragments by molecular structural formula. The approach predicts the pathogenic effect of single amino acid substitutions in proteins related with twenty-five monogenic heritable diseases from the Uniform Screening Panel for Major Conditions recommended by the Advisory Committee on Hereditary Disorders in Newborns and Children. In order to create SSPR models of classification, we modified a piece of cheminformatics software, MultiPASS, that was originally developed for the prediction of activity spectra for drug-like substances. The created SSPR models were compared with traditional bioinformatic tools (SIFT 4G, Polyphen-2 HDIV, MutationAssessor, PROVEAN and FATHMM). The average AUC of our approach was 0.804 ± 0.040. Better quality scores were achieved for 15 from 25 proteins with a significantly higher accuracy for some proteins (IVD, HADHB, HBB). The best SSPR models of classification are freely available in the online resource SAV-Pred (Single Amino acid Variants Predictor).
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(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)
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Open AccessArticle
Anti-Inflammatory Activity and Mechanism of Sweet Corn Extract on Il-1β-Induced Inflammation in a Human Retinal Pigment Epithelial Cell Line (ARPE-19)
by
, , , and
Int. J. Mol. Sci. 2023, 24(3), 2462; https://doi.org/10.3390/ijms24032462 - 27 Jan 2023
Abstract
Age-related macular degeneration (AMD) is an eye disease associated with aging. Development of AMD is related to degeneration and dysfunction of the retinal pigment epithelium (RPE) caused by low-grade chronic inflammation in aged RPE cells leading to visual loss and blindness. Sweet corn
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Age-related macular degeneration (AMD) is an eye disease associated with aging. Development of AMD is related to degeneration and dysfunction of the retinal pigment epithelium (RPE) caused by low-grade chronic inflammation in aged RPE cells leading to visual loss and blindness. Sweet corn is a good source of lutein and zeaxanthin, which were reported to exert various biological activities, including anti-inflammatory activity. The present study aims to investigate the anti-inflammatory activity and mechanisms of SCE to inhibit the production of inflammatory biomarkers related to AMD development. Cells were pretreated with SCE for 1 h followed by stimulation with IL-1β for another 24 h. The results demonstrated that SCE attenuated IL-1β-induced production of IL-6, IL-8, and MCP-1 and the expression of ICAM-1 and iNOS in a dose-dependent manner. In addition, SCE suppressed the phosphorylation of ERK1/2, SAPK/JNK, p38, and NF-κB (p65) in IL-1β-stimulated ARPE-19 cells. These results proved that SCE protected ARPE-19 cells from IL-1β-induced inflammation by inhibiting inflammatory markers partly via suppressing the activation of MAPK and NF-κB signaling pathways. Overall, SCE is a potential agent for the prevention of AMD development, which should be further evaluated in animals.
Full article
(This article belongs to the Special Issue Nutraceuticals in the Prevention and Treatment of Inflammatory Diseases)
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Open AccessArticle
Microbiome Alterations in Alcohol Use Disorder and Alcoholic Liver Disease
by
and
Int. J. Mol. Sci. 2023, 24(3), 2461; https://doi.org/10.3390/ijms24032461 - 27 Jan 2023
Abstract
Microbiome alterations are emerging as one of the most important factors that influence the course of alcohol use disorder (AUD). Recent advances in bioinformatics enable more robust and accurate characterization of changes in the composition of the microbiome. In this study, our objective
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Microbiome alterations are emerging as one of the most important factors that influence the course of alcohol use disorder (AUD). Recent advances in bioinformatics enable more robust and accurate characterization of changes in the composition of the microbiome. In this study, our objective was to provide the most comprehensive and up-to-date evaluation of microbiome alterations associated with AUD and alcoholic liver disease (ALD). To achieve it, we have applied consistent, state of art bioinformatic workflow to raw reads from multiple 16S rRNA sequencing datasets. The study population consisted of 122 patients with AUD, 75 with ALD, 54 with non-alcoholic liver diseases, and 260 healthy controls. We have found several microbiome alterations that were consistent across multiple datasets. The most consistent changes included a significantly lower abundance of multiple butyrate-producing families, including Ruminococcaceae, Lachnospiraceae, and Oscillospiraceae in AUD compared to HC and further reduction of these families in ALD compared with AUD. Other important results include an increase in endotoxin-producing Proteobacteria in AUD, with the ALD group having the largest increase. All of these alterations can potentially contribute to increased intestinal permeability and inflammation associated with AUD and ALD.
Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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