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
Special Issue “Bioinformatics of Unusual DNA and RNA Structures”
Int. J. Mol. Sci. 2024, 25(10), 5226; https://doi.org/10.3390/ijms25105226 (registering DOI) - 10 May 2024
Abstract
Nucleic acids are not only static carriers of genetic information but also play vital roles in controlling cellular lifecycles through their fascinating structural diversity [...]
Full article
(This article belongs to the Special Issue Bioinformatics of Unusual DNA and RNA Structures)
Open AccessArticle
Melatonin Inhibits Hypoxia-Induced Alzheimer’s Disease Pathogenesis by Regulating the Amyloidogenic Pathway in Human Neuroblastoma Cells
by
Nongnuch Singrang, Chutikorn Nopparat, Jiraporn Panmanee and Piyarat Govitrapong
Int. J. Mol. Sci. 2024, 25(10), 5225; https://doi.org/10.3390/ijms25105225 (registering DOI) - 10 May 2024
Abstract
Stroke and Alzheimer's disease (AD) are prevalent age-related diseases; however, the relationship between these two diseases remains unclear. In this study, we aimed to investigate the ability of melatonin, a hormone produced by the pineal gland, to alleviate the effects of ischemic stroke
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Stroke and Alzheimer's disease (AD) are prevalent age-related diseases; however, the relationship between these two diseases remains unclear. In this study, we aimed to investigate the ability of melatonin, a hormone produced by the pineal gland, to alleviate the effects of ischemic stroke leading to AD by observing the pathogenesis of AD hallmarks. We utilized SH-SY5Y cells under the conditions of oxygen–glucose deprivation (OGD) and oxygen-glucose deprivation and reoxygenation (OGD/R) to establish ischemic stroke conditions. We detected that hypoxia-inducible factor-1α (HIF-1α), an indicator of ischemic stroke, was highly upregulated at both the protein and mRNA levels under OGD conditions. Melatonin significantly downregulated both HIF-1α mRNA and protein expression under OGD/R conditions. We detected the upregulation of β-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression under both OGD and OGD/R conditions, while 10 µM of melatonin attenuated these effects and inhibited beta amyloid (Aβ) production. Furthermore, we demonstrated that OGD/R conditions were able to activate the BACE1 promoter, while melatonin inhibited this effect. The present results indicate that melatonin has a significant impact on preventing the aberrant development of ischemic stroke, which can lead to the development of AD, providing new insight into the prevention of AD and potential stroke treatments.
Full article
(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)
Open AccessReview
Molecular Mechanisms of Fetal and Neonatal Lupus: A Narrative Review of an Autoimmune Disease Transferal across the Placenta
by
Armando Di Ludovico, Marta Rinaldi, Francesca Mainieri, Stefano Di Michele, Virginia Girlando, Francesca Ciarelli, Saverio La Bella, Francesco Chiarelli, Marina Attanasi, Angela Mauro, Emanuele Bizzi, Antonio Brucato and Luciana Breda
Int. J. Mol. Sci. 2024, 25(10), 5224; https://doi.org/10.3390/ijms25105224 (registering DOI) - 10 May 2024
Abstract
This study, conducted by searching keywords such as “maternal lupus”, “neonatal lupus”, and “congenital heart block” in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause
[...] Read more.
This study, conducted by searching keywords such as “maternal lupus”, “neonatal lupus”, and “congenital heart block” in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants.
Full article
(This article belongs to the Special Issue Pediatric Rheumatic Diseases: Molecular Basis and Therapies)
Open AccessArticle
NF-κB Decoy Oligodeoxynucleotide-Loaded Poly Lactic-co-glycolic Acid Nanospheres Facilitate Socket Healing in Orthodontic Tooth Movement
by
Albert chun-shuo Huang, Yuji Ishida, Kasumi Hatano-sato, Shuji Oishi, Jun Hosomichi, Risa Usumi-fujita, Hiroyuki Yamaguchi, Hiroyuki Tsujimoto, Aiko Sasai, Ayaka Ochi and Takashi Ono
Int. J. Mol. Sci. 2024, 25(10), 5223; https://doi.org/10.3390/ijms25105223 (registering DOI) - 10 May 2024
Abstract
Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following
[...] Read more.
Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following the bilateral extraction of maxillary first molars in a controlled experiment involving forty rats of OTM model with ethics approved. The decreased tendency of the OTM distance and inclination angle with increased bone volume and improved trabecular bone structure indicated minimized alveolar bone destruction. Reverse transcription-quantitative polymerase chain reaction and histomorphometric analysis demonstrated the suppression of inflammation and bone resorption by downregulating the expression of tartrate-resistant acid phosphatase, tumor necrosis factor-α, interleukin-1β, cathepsin K, NF-κB p65, and receptor activator of NF-κB ligand while provoking periodontal regeneration by upregulating the expression of alkaline phosphatase, transforming growth factor-β1, osteopontin, and fibroblast growth factor-2. Importantly, relative gene expression over the maxillary second molar compression side in proximity to the alveolus highlighted the pharmacological effect of intra-socket PLGA-NfD administration, as evidenced by elevated osteocalcin expression, indicative of enhanced osteocytogenesis. These findings emphasize that locally administered PLGA-NfD serves as an effective inflammatory suppressor and yields periodontal regenerative responses following tooth extraction.
Full article
(This article belongs to the Special Issue Bioactive Nanoparticles: Synthesis and Potential Applications)
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Open AccessReview
Puerarin—A Promising Flavonoid: Biosynthesis, Extraction Methods, Analytical Techniques, and Biological Effects
by
Sergio Liga and Cristina Paul
Int. J. Mol. Sci. 2024, 25(10), 5222; https://doi.org/10.3390/ijms25105222 (registering DOI) - 10 May 2024
Abstract
Flavonoids, a variety of plant secondary metabolites, are known for their diverse biological activities. Isoflavones are a subgroup of flavonoids that have gained attention for their potential health benefits. Puerarin is one of the bioactive isoflavones found in the Kudzu root and Pueraria
[...] Read more.
Flavonoids, a variety of plant secondary metabolites, are known for their diverse biological activities. Isoflavones are a subgroup of flavonoids that have gained attention for their potential health benefits. Puerarin is one of the bioactive isoflavones found in the Kudzu root and Pueraria genus, which is widely used in alternative Chinese medicine, and has been found to be effective in treating chronic conditions like cardiovascular diseases, liver diseases, gastric diseases, respiratory diseases, diabetes, Alzheimer’s disease, and cancer. Puerarin has been extensively researched and used in both scientific and clinical studies over the past few years. The purpose of this review is to provide an up-to-date exploration of puerarin biosynthesis, the most common extraction methods, analytical techniques, and biological effects, which have the potential to provide a new perspective for medical and pharmaceutical research and development.
Full article
(This article belongs to the Special Issue Bioactive Natural Compounds: Protecting Plants and Promoting Human Health)
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Open AccessArticle
Lemon Flavonoid Extract Eriomin Improves Pro/Antioxidant Status and Interferes with Cholesterol Metabolism without Affecting Serum Cholesterol Levels in Aged Rats
by
Branka Šošić-Jurjević, Slavica Borković-Mitić, Slađan Pavlović, Dragana Vlahović, Marko Miler, Thais Cesar, Vladimir Ajdžanović, Dragan Milenkovic, Frans Stellaard, Svetlana Trifunović, Branko Filipović and Dieter Lütjohann
Int. J. Mol. Sci. 2024, 25(10), 5221; https://doi.org/10.3390/ijms25105221 (registering DOI) - 10 May 2024
Abstract
This study aimed to assess the antioxidant capacity of lemon flavonoid extract Eriomin® (LE) and its impact on cholesterol metabolism in the context of healthy aging. We orally treated 24-month-old male Wistar rats with an LE (40 mg/kg) suspended in 0.3 mL
[...] Read more.
This study aimed to assess the antioxidant capacity of lemon flavonoid extract Eriomin® (LE) and its impact on cholesterol metabolism in the context of healthy aging. We orally treated 24-month-old male Wistar rats with an LE (40 mg/kg) suspended in 0.3 mL of sunflower oil. At the same time, control groups received an equal volume of sunflower oil (CON) or remained untreated (ICON) daily for 4 weeks. We examined LE’s effects on superoxide dismutase and catalase- and glutathione-related enzyme activities, the concentration of lipid peroxides and protein carbonyls, total oxidant status (TOS) and antioxidant status (TAS), and oxidative stress index (OSI) in the liver, jejunum, and ileum. We also measured total cholesterol, its biosynthetic precursors (lanosterol, lathosterol, desmosterol), its degradation products (bile acid precursors) in the serum, liver, jejunum, and ileum, and serum phytosterols (intestinal absorption markers). LE reduced TOS, TAS, and OSI (p < 0.05) compared with control values, indicating its consistent antioxidant action in all examined organs. LE lowered hepatic desmosterol (p < 0.05) while also reducing 7α- and 24-hydroxycholesterol levels in the liver and ileum (p < 0.01). Serum cholesterol, hepatic gene expression, and the immunostaining intensity of CYP7A1 were unchanged. In conclusion, LE exerted non-enzymatic antioxidant effects and reduced cholesterol degradation, reducing its biosynthesis products, thereby maintaining serum cholesterol levels.
Full article
(This article belongs to the Special Issue Natural Antioxidants 2.0: Extraction, Optimization, Characterization, and Their Biological Activity)
Open AccessArticle
Interaction between Enrofloxacin and Three Essential Oils (Cinnamon Bark, Clove Bud and Lavender Flower)—A Study on Multidrug-Resistant Escherichia coli Strains Isolated from 1-Day-Old Broiler Chickens
by
Sławomir Zych, Michalina Adaszyńska-Skwirzyńska, Małgorzata Anna Szewczuk and Danuta Szczerbińska
Int. J. Mol. Sci. 2024, 25(10), 5220; https://doi.org/10.3390/ijms25105220 (registering DOI) - 10 May 2024
Abstract
Avian pathogenic Escherichia coli (APEC) causes a variety of infections outside the intestine. The treatment of these infections is becoming increasingly difficult due to the emergence of multi-drug resistant (MDR) strains, which can also be a direct or indirect threat to humans as
[...] Read more.
Avian pathogenic Escherichia coli (APEC) causes a variety of infections outside the intestine. The treatment of these infections is becoming increasingly difficult due to the emergence of multi-drug resistant (MDR) strains, which can also be a direct or indirect threat to humans as consumers of poultry products. Therefore, alternative antimicrobial agents are being sought, which could be essential oils, either administered individually or in interaction with antibiotics. Sixteen field isolates of E. coli (originating from 1-day-old broilers) and the ATCC 25922 reference strain were tested. Commercial cinnamon bark, clove bud, lavender flower essential oils (EOs) and enrofloxacin were selected to assess the sensitivity of the selected E. coli strains to antimicrobial agents. The checkerboard method was used to estimate the individual minimum inhibitory concentration (MIC) for each antimicrobial agent as well as to determine the interactions between the selected essential oil and enrofloxacin. In the case of enrofloxacin, ten isolates were resistant at MIC ≥ 2 μg/mL, three were classified as intermediate (0.5–1 μg/mL) and three as sensitive at ≤0.25 μg/mL. Regardless of the sensitivity to enrofloxacin, the MIC for cinnamon EO was 0.25% v/v and for clove EO was 0.125% v/v. All MDR strains had MIC values for lavender EO of 1% v/v, while drug-sensitive isolates had MIC of 0.5% v/v. Synergism between enrofloxacin and EO was noted more frequently in lavender EO (82.35%), followed by cinnamon EO (64.7%), than in clove EO (47.1%). The remaining cases exhibited additive effects. Owing to synergy, the isolates became susceptible to enrofloxacin at an MIC of ≤8 µg/mL. A time–kill study supports these observations. Cinnamon and clove EOs required for up to 1 h and lavender EO for up to 4 h to completely kill a multidrug-resistant strain as well as the ATCC 25922 reference strain of E. coli. Through synergistic or additive effects, blends with a lower than MIC concentration of enrofloxacin mixed with a lower EO content required 6 ±2 h to achieve a similar effect.
Full article
(This article belongs to the Special Issue Novel Antimicrobial Agents)
Open AccessArticle
Extracellular Vesicles Generated by Mesenchymal Stem Cells in Stirred Suspension Bioreactors Promote Angiogenesis in Human-Brain-Derived Endothelial Cells
by
Jolene Phelps, David A. Hart, Alim P. Mitha, Neil A. Duncan and Arindom Sen
Int. J. Mol. Sci. 2024, 25(10), 5219; https://doi.org/10.3390/ijms25105219 (registering DOI) - 10 May 2024
Abstract
Interrupted blood flow in the brain due to ischemic injuries such as ischemic stroke or traumatic brain injury results in irreversible brain damage, leading to cognitive impairment associated with inflammation, disruption of the blood–brain barrier (BBB), and cell death. Since the BBB only
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Interrupted blood flow in the brain due to ischemic injuries such as ischemic stroke or traumatic brain injury results in irreversible brain damage, leading to cognitive impairment associated with inflammation, disruption of the blood–brain barrier (BBB), and cell death. Since the BBB only allows entry to a small class of drugs, many drugs used to treat ischemia in other tissues have failed in brain-related disorders. The administration of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has shown promise in improving the functional recovery of the brain following cerebral ischemia by inducing blood vessel formation. To facilitate such a treatment approach, it is necessary to develop bioprocesses that can produce therapeutically relevant MSC-EVs in a reproducible and scalable manner. This study evaluated the feasibility of using stirred suspension bioreactors (SSBs) to scale-up the serum-free production of pro-angiogenic MSC-EVs under clinically relevant physioxic conditions. It was found that MSCs grown in SSBs generated EVs that stimulated angiogenesis in cerebral microvascular endothelial cells, supporting the use of SSBs to produce MSC-EVs for application in cerebral ischemia. These properties were impaired at higher cell confluency, outlining the importance of considering the time of harvest when developing bioprocesses to manufacture EV populations.
Full article
(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases 2.0)
Open AccessArticle
Challenges of Robust RNAi-Mediated Gene Silencing in Aedes Mosquitoes
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Lucas Henrique Figueiredo Prates, Jakob Fiebig, Henrik Schlosser, Eleni Liapi, Tanja Rehling, Célia Lutrat, Jeremy Bouyer, Qiang Sun, Han Wen, Zhiyong Xi, Marc F. Schetelig and Irina Häcker
Int. J. Mol. Sci. 2024, 25(10), 5218; https://doi.org/10.3390/ijms25105218 (registering DOI) - 10 May 2024
Abstract
In this study, we report the complexities and challenges associated with achieving robust RNA interference (RNAi)-mediated gene knockdown in the mosquitoes Aedes aegypti and Aedes albopictus, a pivotal approach for genetic analysis and vector control. Despite RNAi’s potential for species-specific gene
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In this study, we report the complexities and challenges associated with achieving robust RNA interference (RNAi)-mediated gene knockdown in the mosquitoes Aedes aegypti and Aedes albopictus, a pivotal approach for genetic analysis and vector control. Despite RNAi’s potential for species-specific gene targeting, our independent efforts to establish oral delivery of RNAi for identifying genes critical for mosquito development and fitness encountered significant challenges, failing to reproduce previously reported potent RNAi effects. We independently evaluated a range of RNAi-inducing molecules (siRNAs, shRNAs, and dsRNAs) and administration methods (oral delivery, immersion, and microinjection) in three different laboratories. We also tested various mosquito strains and utilized microorganisms for RNA delivery. Our results reveal a pronounced inconsistency in RNAi efficacy, characterized by minimal effects on larval survival and gene expression levels in most instances despite strong published effects for the tested targets. One or multiple factors, including RNase activity in the gut, the cellular internalization and processing of RNA molecules, and the systemic dissemination of the RNAi signal, could be involved in this variability, all of which are barely understood in mosquitoes. The challenges identified in this study highlight the necessity for additional research into the underlying mechanisms of mosquito RNAi to develop more robust RNAi-based methodologies. Our findings emphasize the intricacies of RNAi application in mosquitoes, which present a substantial barrier to its utilization in genetic control strategies.
Full article
(This article belongs to the Special Issue Molecular Ecology, Physiology and Biochemistry of Insects, 4th Edition)
Open AccessArticle
Genetic Diversity and Genome-Wide Association Analysis of the Hulled/Naked Trait in a Barley Collection from Shanghai Agricultural Gene Bank
by
Zhiwei Chen, Zhenzhu Guo, Luli Li, Nigel G. Halford, Guimei Guo, Shuwei Zhang, Yingjie Zong, Shiseng Liu, Chenghong Liu and Longhua Zhou
Int. J. Mol. Sci. 2024, 25(10), 5217; https://doi.org/10.3390/ijms25105217 (registering DOI) - 10 May 2024
Abstract
Barley is one of the most important cereal crops in the world, and its value as a food is constantly being revealed, so the research into and the use of barley germplasm are very important for global food security. Although a large number
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Barley is one of the most important cereal crops in the world, and its value as a food is constantly being revealed, so the research into and the use of barley germplasm are very important for global food security. Although a large number of barley germplasm samples have been collected globally, their specific genetic compositions are not well understood, and in many cases their origins are even disputed. In this study, 183 barley germplasm samples from the Shanghai Agricultural Gene Bank were genotyped using genotyping-by-sequencing (GBS) technology, SNPs were identified and their genetic parameters were estimated, principal component analysis (PCA) was preformed, and the phylogenetic tree and population structure of the samples were also analyzed. In addition, a genome-wide association study (GWAS) was carried out for the hulled/naked grain trait, and a KASP marker was developed using an associated SNP. The results showed that a total of 181,906 SNPs were identified, and these barley germplasm samples could be roughly divided into three categories according to the phylogenetic analysis, which was generally consistent with the classification of the traits of row type and hulled/naked grain. Population structure analysis showed that the whole barley population could be divided into four sub-populations (SPs), the main difference from previous classifications being that the two-rowed and the hulled genotypes were sub-divided into two SPs. The GWAS analysis of the hulled/naked trait showed that many associated loci were unrelated to the Nud/nud locus, indicating that there might be new loci controlling the trait. A KASP marker was developed for one exon-type SNP on chromosome 7. Genotyping based on the KASP assay was consistent with that based on SNPs, indicating that the gene of this locus might be associated with the hulled/naked trait. The above work not only lays a good foundation for the future utilization of this barley germplasm population but it provides new loci and candidate genes for the hulled/naked trait.
Full article
(This article belongs to the Collection Advances in Molecular Plant Sciences)
Open AccessFeature PaperArticle
Development of a Robust Read-Across Model for the Prediction of Biological Potency of Novel Peroxisome Proliferator-Activated Receptor Delta Agonists
by
Maria Antoniou, Konstantinos D. Papavasileiou, Georgia Melagraki, Francesco Dondero, Iseult Lynch and Antreas Afantitis
Int. J. Mol. Sci. 2024, 25(10), 5216; https://doi.org/10.3390/ijms25105216 (registering DOI) - 10 May 2024
Abstract
A robust predictive model was developed using 136 novel peroxisome proliferator-activated receptor delta (PPARδ) agonists, a distinct subtype of lipid-activated transcription factors of the nuclear receptor superfamily that regulate target genes by binding to characteristic sequences of DNA bases. The model employs various
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A robust predictive model was developed using 136 novel peroxisome proliferator-activated receptor delta (PPARδ) agonists, a distinct subtype of lipid-activated transcription factors of the nuclear receptor superfamily that regulate target genes by binding to characteristic sequences of DNA bases. The model employs various structural descriptors and docking calculations and provides predictions of the biological activity of PPARδ agonists, following the criteria of the Organization for Economic Co-operation and Development (OECD) for the development and validation of quantitative structure–activity relationship (QSAR) models. Specifically focused on small molecules, the model facilitates the identification of highly potent and selective PPARδ agonists and offers a read-across concept by providing the chemical neighbours of the compound under study. The model development process was conducted on Isalos Analytics Software (v. 0.1.17) which provides an intuitive environment for machine-learning applications. The final model was released as a user-friendly web tool and can be accessed through the Enalos Cloud platform’s graphical user interface (GUI).
Full article
(This article belongs to the Special Issue Cheminformatics in Drug Discovery and Material Design)
Open AccessArticle
Leptin Promotes Vasculogenic Mimicry in Breast Cancer Cells by Regulating Aquaporin-1
by
Deok-Soo Han and Eun-Ok Lee
Int. J. Mol. Sci. 2024, 25(10), 5215; https://doi.org/10.3390/ijms25105215 (registering DOI) - 10 May 2024
Abstract
Leptin is an obesity-related hormone that plays an important role in breast cancer progression. Vasculogenic mimicry (VM) refers to the formation of vascular channels lined by tumor cells. This study aimed to investigate the relationship between leptin and VM in human breast cancer
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Leptin is an obesity-related hormone that plays an important role in breast cancer progression. Vasculogenic mimicry (VM) refers to the formation of vascular channels lined by tumor cells. This study aimed to investigate the relationship between leptin and VM in human breast cancer cells. VM was measured by a 3D culture assay. Signal transducers and activators of transcription 3 (STAT3) signaling, aquaporin-1 (AQP1), and the expression of VM-related proteins, including vascular endothelial cadherin (VE-cadherin), twist, matrix metalloproteinase-2 (MMP-2), and laminin subunit 5 gamma-2 (LAMC2), were examined by Western blot. AQP1 mRNA was analyzed by a reverse transcriptase-polymerase chain reaction (RT-PCR). Leptin increased VM and upregulated phospho-STAT3, VE-cadherin, twist, MMP-2, and LAMC2. These effects were inhibited by the leptin receptor-blocking peptide, Ob-R BP, and the STAT3 inhibitor, AG490. A positive correlation between leptin and AQP1 mRNA was observed and was confirmed by RT-PCR. Leptin upregulated AQP1 expression, which was blocked by Ob-R BP and AG490. AQP1 overexpression increased VM and the expression of VM-related proteins. AQP1 silencing inhibited leptin-induced VM and the expression of VM-related proteins. Thus, these results showed that leptin facilitates VM in breast cancer cells via the Ob-R/STAT3 pathway and that AQP1 is a key mediator in leptin-induced VM.
Full article
(This article belongs to the Special Issue Cancer Biomarkers and Bioinformatics)
Open AccessArticle
Mucolytic Drugs Ambroxol and Bromhexine: Transformation under Aqueous Chlorination Conditions
by
Sergey A. Sypalov, Ilya S. Varsegov, Nikolay V. Ulyanovskii, Albert T. Lebedev and Dmitry S. Kosyakov
Int. J. Mol. Sci. 2024, 25(10), 5214; https://doi.org/10.3390/ijms25105214 (registering DOI) - 10 May 2024
Abstract
Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous
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Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure.
Full article
(This article belongs to the Section Molecular Pharmacology)
Open AccessReview
Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics
by
Jesús David Urbano-Gámez, Cinzia Guzzi, Manuel Bernal, Juan Solivera, Iñigo Martínez-Zubiaurre, Carlos Caro and María Luisa García-Martín
Int. J. Mol. Sci. 2024, 25(10), 5213; https://doi.org/10.3390/ijms25105213 (registering DOI) - 10 May 2024
Abstract
The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor,
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The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of “tumor targeting” and “tumor cell targeting” are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where ‘smart design’ refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.
Full article
(This article belongs to the Special Issue Application of Nanostructures in Biology and Medicine)
Open AccessReview
Broader Perspective on Atherosclerosis—Selected Risk Factors, Biomarkers, and Therapeutic Approach
by
Piotr Fularski, Witold Czarnik, Bartłomiej Dąbek, Wiktoria Lisińska, Ewa Radzioch, Alicja Witkowska, Ewelina Młynarska, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2024, 25(10), 5212; https://doi.org/10.3390/ijms25105212 (registering DOI) - 10 May 2024
Abstract
Atherosclerotic cardiovascular disease (ASCVD) stands as the leading cause of mortality worldwide. At its core lies a progressive process of atherosclerosis, influenced by multiple factors. Among them, lifestyle-related factors are highlighted, with inadequate diet being one of the foremost, alongside factors such as
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Atherosclerotic cardiovascular disease (ASCVD) stands as the leading cause of mortality worldwide. At its core lies a progressive process of atherosclerosis, influenced by multiple factors. Among them, lifestyle-related factors are highlighted, with inadequate diet being one of the foremost, alongside factors such as cigarette smoking, low physical activity, and sleep deprivation. Another substantial group of risk factors comprises comorbidities. Amongst others, conditions such as hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), or familial hypercholesterolemia (FH) are included here. Extremely significant in the context of halting progression is counteracting the mentioned risk factors, including through treatment of the underlying disease. What is more, in recent years, there has been increasing attention paid to perceiving atherosclerosis as an inflammation-related disease. Consequently, efforts are directed towards exploring new anti-inflammatory medications to limit ASCVD progression. Simultaneously, research is underway to identify biomarkers capable of providing insights into the ongoing process of atherosclerotic plaque formation. The aim of this study is to provide a broader perspective on ASCVD, particularly focusing on its characteristics, traditional and novel treatment methods, and biomarkers that can facilitate its early detection.
Full article
(This article belongs to the Special Issue Molecular Advances in the Diagnosis and Drug Therapies of Atherosclerotic Cardiovascular Diseases (ASCVD))
Open AccessArticle
Investigating Distinct Skin Microbial Communities and Skin Metabolome Profiles in Atopic Dermatitis
by
Suyeon Kim, Minah Cho, Eun Sung Jung, Inseon Sim and Yu Ri Woo
Int. J. Mol. Sci. 2024, 25(10), 5211; https://doi.org/10.3390/ijms25105211 (registering DOI) - 10 May 2024
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic predisposition, environmental factors, immune dysregulation, and skin barrier dysfunction. The skin microbiome and metabolome play crucial roles in modulating the skin’s immune environment and integrity. However, their specific contributions to AD
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Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic predisposition, environmental factors, immune dysregulation, and skin barrier dysfunction. The skin microbiome and metabolome play crucial roles in modulating the skin’s immune environment and integrity. However, their specific contributions to AD remain unclear. We aimed to investigate the distinct skin microbial communities and skin metabolic compounds in AD patients compared to healthy controls (HCs). Seven patients with AD patients and seven HCs were enrolled, from whom skin samples were obtained for examination. The study involved 16S rRNA metagenomic sequencing and bioinformatics analysis as well as the use of gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) to detect metabolites associated with AD in the skin. We observed significant differences in microbial diversity between lesional and non-lesional skin of AD patients and HCs. Staphylococcus overgrowth was prominent in AD lesions, while Cutibacterium levels were decreased. Metabolomic analysis revealed elevated levels of several metabolites, including hypoxanthine and glycerol-3-phosphate in AD lesions, indicating perturbations in purine metabolism and energy production pathways. Moreover, we found a positive correlation between hypoxanthine and glycerol-3-phosphate and clinical severity of AD and Staphylococcus overgrowth. These findings suggest potential biomarkers for monitoring AD severity. Further research is needed to elucidate the causal relationships between microbial dysbiosis, metabolic alterations, and AD progression, paving the way for targeted therapeutic interventions.
Full article
(This article belongs to the Special Issue Molecular Research Progress of Skin and Skin Diseases)
Open AccessReview
Immunology of Physical Exercise: Is Equus caballus an Appropriate Animal Model for Human Athletes?
by
Olga Witkowska-Piłaszewicz, Katarzyna Malin, Izabela Dąbrowska, Jowita Grzędzicka, Piotr Ostaszewski and Craig Carter
Int. J. Mol. Sci. 2024, 25(10), 5210; https://doi.org/10.3390/ijms25105210 (registering DOI) - 10 May 2024
Abstract
Domestic horses routinely participate in vigorous and various athletic activities. This enables the horse to serve as a model for studying athletic physiology and immunology in other species, including humans. For instance, as a model of physical efforts, such as endurance rides (long-distance
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Domestic horses routinely participate in vigorous and various athletic activities. This enables the horse to serve as a model for studying athletic physiology and immunology in other species, including humans. For instance, as a model of physical efforts, such as endurance rides (long-distance running/aerobic exercise) and races (anaerobic exercise), the horse can be useful in evaluating post-exercise response. Currently, there has been significant interest in finding biomarkers, which characterize the advancement of training and adaptation to physical exercise in the horse. The parallels in cellular responses to physical exercises, such as changes in receptor expression and blood cell activity, improve our understanding of the mechanisms involved in the body’s response to intense physical activity. This study focuses on the changes in levels of the pro- and anti-inflammatory cytokines and cellular response in the context of post-exercise immune response. Both the direction of changes in cytokine levels and cellular responses of the body, such as proliferation and expression of surface markers on lymphocytes, monocytes and neutrophils, show cross-functional similarities. This review reveals that horses are robust research models for studying the immune response to physical exercise in human athletes.
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(This article belongs to the Special Issue Pharmacological Approaches and Models of Physical Activity in the Treatment of Inflammatory Diseases and Cancer)
Open AccessArticle
Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei
by
Inês Costa, Inês Lopes, Mariana Morais, Renata Silva, Fernando Remião, Rui Medeiros, Luís G. Alves, Eugénia Pinto and Fátima Cerqueira
Int. J. Mol. Sci. 2024, 25(10), 5209; https://doi.org/10.3390/ijms25105209 (registering DOI) - 10 May 2024
Abstract
Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority
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Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 µg/mL for C. krusei and of 128 µg/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 mg/mL and a HC10 value against human red blood cells of 0.8 mg/mL.
Full article
(This article belongs to the Special Issue Antifungal Drug Design, Synthesis and Molecular Mechanisms)
Open AccessReview
Liquid Biopsies as Non-Invasive Tools for Mutation Profiling in Multiple Myeloma: Application Potential, Challenges, and Opportunities
by
Robbe Heestermans, Rik Schots, Ann De Becker and Ivan Van Riet
Int. J. Mol. Sci. 2024, 25(10), 5208; https://doi.org/10.3390/ijms25105208 (registering DOI) - 10 May 2024
Abstract
Over the last decades, the survival of multiple myeloma (MM) patients has considerably improved. However, despite the availability of new treatments, most patients still relapse and become therapy-resistant at some point in the disease evolution. The mutation profile has an impact on MM
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Over the last decades, the survival of multiple myeloma (MM) patients has considerably improved. However, despite the availability of new treatments, most patients still relapse and become therapy-resistant at some point in the disease evolution. The mutation profile has an impact on MM patients’ outcome, while typically evolving over time. Because of the patchy bone marrow (BM) infiltration pattern, the analysis of a single bone marrow sample can lead to an underestimation of the known genetic heterogeneity in MM. As a result, interest is shifting towards blood-derived liquid biopsies, which allow for a more comprehensive and non-invasive genetic interrogation without the discomfort of repeated BM aspirations. In this review, we compare the application potential for mutation profiling in MM of circulating-tumor-cell-derived DNA, cell-free DNA and extracellular-vesicle-derived DNA, while also addressing the challenges associated with their use.
Full article
(This article belongs to the Special Issue Liquid Biopsy in the Approach of Non-communicable Chronic Diseases (NCCD) and Cancer)
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Open AccessArticle
MEF2D Functions as a Tumor Suppressor in Breast Cancer
by
Xiaoxia Wang, He Shen, Yanmin Chen, Yali Zhang, Jianmin Wang, Song Liu, Bo Xu, Hai Wang, Costa Frangou and Jianmin Zhang
Int. J. Mol. Sci. 2024, 25(10), 5207; https://doi.org/10.3390/ijms25105207 (registering DOI) - 10 May 2024
Abstract
The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by
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The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by acting as oncogenes or tumor suppressors depending on the biological context. Nonetheless, the molecular programs they regulate and their roles in tumor development and progression remain incompletely understood. The present study evaluated whether the MEF2D transcription factor functions as a tumor suppressor in breast cancer. The knockout of the MEF2D gene in mouse mammary epithelial cells resulted in phenotypic changes characteristic of neoplastic transformation. These changes included enhanced cell proliferation, a loss of contact inhibition, and anchorage-independent growth in soft agar, as well as the capacity for tumor development in mice. Mechanistically, the knockout of MEF2D induced the epithelial-to-mesenchymal transition (EMT) and activated several oncogenic signaling pathways, including AKT, ERK, and Hippo-YAP. Correspondingly, a reduced expression of MEF2D was observed in human triple-negative breast cancer cell lines, and a low MEF2D expression in tissue samples was found to be correlated with a worse overall survival and relapse-free survival in breast cancer patients. MEF2D may, thus, be a putative tumor suppressor, acting through selective gene regulatory programs that have clinical and therapeutic significance.
Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer: Pathophysiology and Treatment)
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