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
Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study
Int. J. Mol. Sci. 2024, 25(9), 5038; https://doi.org/10.3390/ijms25095038 (registering DOI) - 05 May 2024
Abstract
In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly
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In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1–5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-β by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1β levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3–407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9–220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03–164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9–349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1β suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.
Full article
(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action 2.0)
Open AccessReview
Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications
by
Yi-Hsin Chen, Kang-Hsi Wu and Han-Ping Wu
Int. J. Mol. Sci. 2024, 25(9), 5037; https://doi.org/10.3390/ijms25095037 (registering DOI) - 05 May 2024
Abstract
Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing
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Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases.
Full article
(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)
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Open AccessArticle
Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making
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Rosa Miquel-Rodríguez, Beatriz González-Toledo, María-Vanessa Pérez-Gómez, Marian Cobo, Patricia Delgado-Mallén, Sara Estupiñán, Coriolano Cruz-Perera, Laura Díaz-Martín, Federico González-Rinne, Alejandra González-Delgado, Armando Torres, Flavio Gaspari, Domingo Hernández-Marrero, Alberto Ortiz, Esteban Porrini and Sergio Luis-Lima
Int. J. Mol. Sci. 2024, 25(9), 5036; https://doi.org/10.3390/ijms25095036 (registering DOI) - 05 May 2024
Abstract
Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration
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Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (−3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.
Full article
(This article belongs to the Special Issue Etiology and Research Progress of Chronic Kidney Disease)
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Open AccessArticle
Comparison of Muscle Regeneration Effects at Different Melittin Concentrations in Rabbit Atrophied Muscle
by
Byeong-Churl Jang, Eun Sang Kwon, Yoon-Jin Lee, Jae Ik Jung, Yong Seok Moon and Dong Rak Kwon
Int. J. Mol. Sci. 2024, 25(9), 5035; https://doi.org/10.3390/ijms25095035 (registering DOI) - 05 May 2024
Abstract
This research aimed to explore the healing impacts of Melittin treatment on gastrocnemius muscle wasting caused by immobilization with a cast in rabbits. Twenty-four rabbits were randomly allocated to four groups. The procedures included different injections: 0.2 mL of normal saline to Group
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This research aimed to explore the healing impacts of Melittin treatment on gastrocnemius muscle wasting caused by immobilization with a cast in rabbits. Twenty-four rabbits were randomly allocated to four groups. The procedures included different injections: 0.2 mL of normal saline to Group 1 (G1-NS); 4 μg/kg of Melittin to Group 2 (G2-4 μg/kg Melittin); 20 μg/kg of Melittin to Group 3 (G3-20 μg/kg Melittin); and 100 μg/kg of Melittin to Group 4 (G4-100 μg/kg Melittin). Ultrasound was used to guide the injections into the rabbits’ atrophied calf muscles following two weeks of immobilization via casting. Clinical measurements, including the length of the calf, the compound muscle action potential (CMAP) of the tibial nerve, and the gastrocnemius muscle thickness, were assessed. Additionally, cross-sectional slices of gastrocnemius muscle fibers were examined, and immunohistochemistry and Western blot analyses were performed following two weeks of therapy. The mean regenerative changes, as indicated by clinical parameters, in Group 4 were significantly more pronounced than in the other groups (p < 0.05). Furthermore, the cross-sectional area of the gastrocnemius muscle fibers and immunohistochemical indicators in Group 4 exceeded those in the remaining groups (p < 0.05). Western blot analysis also showed a more significant presence of anti-inflammatory and angiogenic cytokines in Group 4 compared to the others (p < 0.05). Melittin therapy at a higher dosage can more efficiently activate regeneration in atrophied gastrocnemius muscle compared to lower doses of Melittin or normal saline.
Full article
(This article belongs to the Special Issue Advanced Research on Regenerative Medicine)
Open AccessArticle
Interleukin-13 Treatment of Living Lung Tissue Model Alters the Metabolome and Proteome—A Nano-DESI MS Metabolomics and Shotgun Proteomics Study
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Gábor Tóth, Anastasia Golubova, Alexander Falk, Sara Bergström Lind, Mark Nicholas and Ingela Lanekoff
Int. J. Mol. Sci. 2024, 25(9), 5034; https://doi.org/10.3390/ijms25095034 (registering DOI) - 05 May 2024
Abstract
Asthma is a chronic respiratory disease with one of the largest numbers of cases in the world; thus, constant investigation and technical development are needed to unravel the underlying biochemical mechanisms. In this study, we aimed to develop a nano-DESI MS method for
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Asthma is a chronic respiratory disease with one of the largest numbers of cases in the world; thus, constant investigation and technical development are needed to unravel the underlying biochemical mechanisms. In this study, we aimed to develop a nano-DESI MS method for the in vivo characterization of the cellular metabolome. Using air–liquid interface (ALI) cell layers, we studied the role of Interleukin-13 (IL-13) on differentiated lung epithelial cells acting as a lung tissue model. We demonstrate the feasibility of nano-DESI MS for the in vivo monitoring of basal–apical molecular transport, and the subsequent endogenous metabolic response, for the first time. Conserving the integrity of the ALI lung-cell layer enabled us to perform temporally resolved metabolomic characterization followed by “bottom-up” proteomics on the same population of cells. Metabolic remodeling was observed upon histamine and corticosteroid treatment of the IL-13-exposed lung cell monolayers, in correlation with alterations in the proteomic profile. This proof of principle study demonstrates the utility of in vivo nano-DESI MS for characterizing ALI tissue layers, and the new markers identified in our study provide a good starting point for future, larger-scale studies.
Full article
(This article belongs to the Special Issue Metabolomics in Health and Disease 2.0)
Open AccessArticle
Amyloid Beta Leads to Decreased Acetylcholine Levels and Non-Small Cell Lung Cancer Cell Survival via a Mechanism That Involves p38 Mitogen-Activated Protein Kinase and Protein Kinase C in a p53-Dependent and -Independent Manner
by
Hind Al Khashali, Ravel Ray, Ban Darweesh, Caroline Wozniak, Ben Haddad, Stuti Goel, Issah Seidu, Jeneen Khalil, Brooke Lopo, Nayrooz Murshed, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans
Int. J. Mol. Sci. 2024, 25(9), 5033; https://doi.org/10.3390/ijms25095033 (registering DOI) - 05 May 2024
Abstract
Several studies have shown an inverse correlation between the likelihood of developing a neurodegenerative disorder and cancer. We previously reported that the levels of amyloid beta (Aβ), at the center of Alzheimer’s disease pathophysiology, are regulated by acetylcholinesterase (AChE) in non-small cell lung
[...] Read more.
Several studies have shown an inverse correlation between the likelihood of developing a neurodegenerative disorder and cancer. We previously reported that the levels of amyloid beta (Aβ), at the center of Alzheimer’s disease pathophysiology, are regulated by acetylcholinesterase (AChE) in non-small cell lung cancer (NSCLC). Here, we examined the effect of Aβ or its fragments on the levels of ACh in A549 (p53 wild-type) and H1299 (p53-null) NSCLC cell media. ACh levels were reduced by cell treatment with Aβ 1–42, Aβ 1–40, Aβ 1–28, and Aβ 25–35. AChE and p53 activities increased upon A549 cell treatment with Aβ, while knockdown of p53 in A549 cells increased ACh levels, decreased AChE activity, and diminished the Aβ effects. Aβ increased the ratio of phospho/total p38 MAPK and decreased the activity of PKC. Inhibiting p38 MAPK reduced the activity of p53 in A549 cells and increased ACh levels in the media of both cell lines, while opposite effects were found upon inhibiting PKC. ACh decreased the activity of p53 in A549 cells, decreased p38 MAPK activity, increased PKC activity, and diminished the effect of Aβ on those activities. Moreover, the negative effect of Aβ on cell viability was diminished by cell co-treatment with ACh.
Full article
(This article belongs to the Special Issue Role of p53 Family in Targeted Therapy of Cancers)
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Open AccessArticle
Penifuranone A: A Novel Alkaloid from the Mangrove Endophytic Fungus Penicillium crustosum SCNU-F0006
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Hao Jia, Li Wu, Rongrong Liu, Jialin Li, Lingling Liu, Chen Chen, Junsen Li, Kai Zhang, Junjiang Liao and Yuhua Long
Int. J. Mol. Sci. 2024, 25(9), 5032; https://doi.org/10.3390/ijms25095032 (registering DOI) - 05 May 2024
Abstract
One previously undescribed alkaloid, named penifuranone A (1), and three known compounds (2–4) were isolated from the mangrove endophytic fungus Penicillium crustosum SCNU-F0006. The structure of the new alkaloid (1) was elucidated based on extensive spectroscopic
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One previously undescribed alkaloid, named penifuranone A (1), and three known compounds (2–4) were isolated from the mangrove endophytic fungus Penicillium crustosum SCNU-F0006. The structure of the new alkaloid (1) was elucidated based on extensive spectroscopic data analysis and single-crystal X-ray diffraction analysis. Four natural isolates and one new synthetic derivative of penifuranone A, compound 1a, were screened for their antimicrobial, antioxidant, and anti-inflammatory activities. Bioassays revealed that penifuranone A (1) exhibited strong anti-inflammatory activity in vitro by inhibiting nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells with an IC50 value of 42.2 μM. The docking study revealed that compound 1 exhibited an ideal fit within the active site of the murine inducible nitric oxide synthase (iNOS), establishing characteristic hydrogen bonds.
Full article
(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development 2.0)
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Open AccessArticle
TGF-β2 Induces Ribosome Activity, Alters Ribosome Composition and Inhibits IRES-Mediated Translation in Chondrocytes
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Guus G. H. van den Akker, Alzbeta Chabronova, Bas A. C. Housmans, Laura van der Vloet, Don A. M. Surtel, Andy Cremers, Virginie Marchand, Yuri Motorin, Marjolein M. J. Caron, Mandy J. Peffers and Tim. J. M. Welting
Int. J. Mol. Sci. 2024, 25(9), 5031; https://doi.org/10.3390/ijms25095031 (registering DOI) - 05 May 2024
Abstract
Alterations in cell fate are often attributed to (epigenetic) regulation of gene expression. An emerging paradigm focuses on specialized ribosomes within a cell. However, little evidence exists for the dynamic regulation of ribosome composition and function. Here, we stimulated a chondrocytic cell line
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Alterations in cell fate are often attributed to (epigenetic) regulation of gene expression. An emerging paradigm focuses on specialized ribosomes within a cell. However, little evidence exists for the dynamic regulation of ribosome composition and function. Here, we stimulated a chondrocytic cell line with transforming growth factor beta (TGF-β2) and mapped changes in ribosome function, composition and ribosomal RNA (rRNA) epitranscriptomics. 35S Met/Cys incorporation was used to evaluate ribosome activity. Dual luciferase reporter assays were used to assess ribosomal modus. Ribosomal RNA expression and processing were determined by RT-qPCR, while RiboMethSeq and HydraPsiSeq were used to determine rRNA modification profiles. Label-free protein quantification of total cell lysates, isolated ribosomes and secreted proteins was done by LC-MS/MS. A three-day TGF-β2 stimulation induced total protein synthesis in SW1353 chondrocytic cells and human articular chondrocytes. Specifically, TGF-β2 induced cap-mediated protein synthesis, while IRES-mediated translation was not (P53 IRES) or little affected (CrPv IGR and HCV IRES). Three rRNA post-transcriptional modifications (PTMs) were affected by TGF-β2 stimulation (18S-Gm1447 downregulated, 18S-ψ1177 and 28S-ψ4598 upregulated). Proteomic analysis of isolated ribosomes revealed increased interaction with eIF2 and tRNA ligases and decreased association of eIF4A3 and heterogeneous nuclear ribonucleoprotein (HNRNP)s. In addition, thirteen core ribosomal proteins were more present in ribosomes from TGF-β2 stimulated cells, albeit with a modest fold change. A prolonged stimulation of chondrocytic cells with TGF-β2 induced ribosome activity and changed the mode of translation. These functional changes could be coupled to alterations in accessory proteins in the ribosomal proteome.
Full article
(This article belongs to the Special Issue The Evolving Ribosome Concept)
Open AccessArticle
Mitral Cell Dendritic Morphology in the Adult Zebrafish Olfactory Bulb following Growth, Injury and Recovery
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John P. Rozofsky, Joanna M. Pozzuto and Christine A. Byrd-Jacobs
Int. J. Mol. Sci. 2024, 25(9), 5030; https://doi.org/10.3390/ijms25095030 (registering DOI) - 05 May 2024
Abstract
The role of afferent target interactions in dendritic plasticity within the adult brain remains poorly understood. There is a paucity of data regarding the effects of deafferentation and subsequent dendritic recovery in adult brain structures. Moreover, although adult zebrafish demonstrate ongoing growth, investigations
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The role of afferent target interactions in dendritic plasticity within the adult brain remains poorly understood. There is a paucity of data regarding the effects of deafferentation and subsequent dendritic recovery in adult brain structures. Moreover, although adult zebrafish demonstrate ongoing growth, investigations into the impact of growth on mitral cell (MC) dendritic arbor structure and complexity are lacking. Leveraging the regenerative capabilities of the zebrafish olfactory system, we conducted a comprehensive study to address these gaps. Employing an eight-week reversible deafferentation injury model followed by retrograde labeling, we observed substantial morphological alterations in MC dendrites. Our hypothesis posited that cessation of injury would facilitate recovery of MC dendritic arbor structure and complexity, potentially influenced by growth dynamics. Statistical analyses revealed significant changes in MC dendritic morphology following growth and recovery periods, indicating that MC total dendritic branch length retained significance after 8 weeks of deafferentation injury when normalized to individual fish physical characteristics. This suggests that regeneration of branch length could potentially function relatively independently of growth-related changes. These findings underscore the remarkable plasticity of adult dendritic arbor structures in a sophisticated model organism and highlight the efficacy of zebrafish as a vital implement for studying neuroregenerative processes.
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(This article belongs to the Special Issue Zebrafish: A Model Organism for Human Health and Disease)
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Open AccessArticle
Shading Treatment Reduces Grape Sugar Content by Suppressing Photosynthesis-Antenna Protein Pathway Gene Expression in Grape Berries
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Xintong Nan, Wenfang Li, Miao Shao, Zimeng Cui, Han Wang, Jiaxing Huo, Lizhen Chen, Baihong Chen and Zonghuan Ma
Int. J. Mol. Sci. 2024, 25(9), 5029; https://doi.org/10.3390/ijms25095029 (registering DOI) - 05 May 2024
Abstract
To explore the impact of shade treatment on grape berries, ‘Marselan’ grape berries were bagged under different light transmission rates (100% (CK), 75% (A), 50% (B), 25% (C), 0% (D)). It was observed that this treatment delayed the ripening of the grape berries.
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To explore the impact of shade treatment on grape berries, ‘Marselan’ grape berries were bagged under different light transmission rates (100% (CK), 75% (A), 50% (B), 25% (C), 0% (D)). It was observed that this treatment delayed the ripening of the grape berries. The individual weight of the grape berries, as well as the content of fructose, glucose, soluble sugars, and organic acids in the berries, was measured at 90, 100, and 125 days after flowering (DAF90, DAF100, DAF125). The results revealed that shading treatment reduced the sugar content in grape berries; the levels of fructose and glucose were higher in the CK treatment compared to the other treatments, and they increased with the duration of the shading treatment. Conversely, the sucrose content exhibited the opposite trend. Additionally, as the weight of the grape berries increased, the content of soluble solids and soluble sugars in the berries also increased, while the titratable acidity decreased. Furthermore, 16 differentially expressed genes (DEGs) were identified in the photosynthesis-antenna protein pathway from the transcriptome sequencing data. Correlation analysis revealed that the expression levels of genes VIT_08s0007g02190 (Lhcb4) and VIT_15s0024g00040 (Lhca3) were positively correlated with sugar content in the berries at DAF100, but negatively correlated at DAF125. qRT-PCR results confirmed the correlation analysis. This indicates that shading grape clusters inhibits the expression of genes in the photosynthesis-antenna protein pathway in the grape berries, leading to a decrease in sugar content. This finding contributes to a deeper understanding of the impact mechanisms of grape cluster shading on berry quality, providing important scientific grounds for improving grape berry quality.
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(This article belongs to the Section Molecular Plant Sciences)
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Impact of Nebulization on the Physicochemical Properties of Polymer–Lipid Hybrid Nanoparticles for Pulmonary Drug Delivery
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Andrea Gonsalves and Jyothi U. Menon
Int. J. Mol. Sci. 2024, 25(9), 5028; https://doi.org/10.3390/ijms25095028 (registering DOI) - 05 May 2024
Abstract
Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to
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Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to lung diseases. However, there are limited studies evaluating the physicochemical properties of NPs after they are passed through a nebulizer. High shear stress generated during nebulization could potentially affect the surface properties of NPs, resulting in the loss of encapsulated drugs and alteration in the release kinetics. Herein, we thoroughly examined the physicochemical properties as well as the therapeutic effectiveness of Infasurf lung surfactant (IFS)-coated PLGA NPs previously developed by us after passing through a commercial Aeroneb® vibrating-mesh nebulizer. Nebulization did not alter the size, surface charge, IFS coating and bi-phasic release pattern exhibited by the NPs. However, there was a temporary reduction in the initial release of encapsulated therapeutics in the nebulized compared to non-nebulized NPs. This underscores the importance of evaluating the drug release kinetics of NPs using the inhalation method of choice to ensure suitability for the intended medical application. The cellular uptake studies demonstrated that both nebulized and non-nebulized NPs were less readily taken up by alveolar macrophages compared to lung cancer cells, confirming the IFS coating retention. Overall, nebulization did not significantly compromise the physicochemical properties as well as therapeutic efficacy of the prepared nanotherapeutics.
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(This article belongs to the Special Issue Pharmaceutical Nanoimaging and Nanoengineering)
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Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus
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Patryk Graczyk, Aleksandra Dach, Kamil Dyrka and Andrzej Pawlik
Int. J. Mol. Sci. 2024, 25(9), 5027; https://doi.org/10.3390/ijms25095027 (registering DOI) - 05 May 2024
Abstract
Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases
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Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle—a well-balanced diet and physical activity. There is also a group of compounds—including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others—that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.
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(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessEditorial
Strategies to Counteract Oxidative Stress and Inflammation in Chronic-Degenerative Diseases 2.0
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Cecilia Prata, Cristina Angeloni and Tullia Maraldi
Int. J. Mol. Sci. 2024, 25(9), 5026; https://doi.org/10.3390/ijms25095026 (registering DOI) - 04 May 2024
Abstract
Oxidative stress and inflammation are recognized as pivotal contributors and common features of several chronic degenerative diseases, including cancer, metabolic syndrome, type 2 diabetes, cardiovascular diseases and neurodegenerative disorders, affecting a high percentage of the population [...]
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(This article belongs to the Special Issue Strategies to Counteract Oxidative Stress and Inflammation in Chronic-Degenerative Diseases 2.0)
Open AccessArticle
Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome
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Irene Valdivia Callejon, Lucia Buccioli, Jarl Bastianen, Jolien Schippers, Aline Verstraeten, Ilse Luyckx, Silke Peeters, Jan A. H. Danser, Roland R. J. Van Kimmenade, Josephina Meester and Bart Loeys
Int. J. Mol. Sci. 2024, 25(9), 5025; https://doi.org/10.3390/ijms25095025 (registering DOI) - 04 May 2024
Abstract
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin
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Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
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(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)
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Polydopamine/SWCNT Ink Functionalization of Silk Fabric to Obtain Electroconductivity at a Low Percolation Threshold
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Anna Baranowska-Korczyc, Dorota Kowalczyk and Małgorzata Cieślak
Int. J. Mol. Sci. 2024, 25(9), 5024; https://doi.org/10.3390/ijms25095024 (registering DOI) - 04 May 2024
Abstract
This study presents the functionalization of silk fabric with SWCNT ink. The first step was the formation of a polydopamine (PDA) thin coating on the silk fabric to allow for effective bonding of SWCNTs. PDA formation was carried out directly on the fabric
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This study presents the functionalization of silk fabric with SWCNT ink. The first step was the formation of a polydopamine (PDA) thin coating on the silk fabric to allow for effective bonding of SWCNTs. PDA formation was carried out directly on the fabric by means of polymerization of dopamine in alkali conditions. The Silk/PDA fabric was functionalized with SWCNT ink of different SWCNT concentrations by using the dip-coating method. IR and Raman analyses show that the dominant β-sheet structure of silk fibroin after the functionalization process remains unchanged. The heat resistance is even slightly improved. The hydrophobic silk fabric becomes hydrophilic after functionalization due to the influence of PDA and the surfactant in SWCNT ink. The ink significantly changes the electrical properties of the silk fabric, from insulating to conductive. The volume resistance changes by nine orders of magnitude, from 2.4 × 1012 Ω to 2.3 × 103 Ω for 0.12 wt.% of SWCNTs. The surface resistance changes by seven orders of magnitude, from 2.1 × 1012 Ω to 2.4 × 105 Ω for 0.17 wt.% of SWCNTs. The volume and surface resistance thresholds are determined to be about 0.05 wt.% and 0.06 wt.%, respectively. The low value of the percolation threshold indicates efficient functionalization, with high-quality ink facilitating the formation of percolation paths through SWCNTs and the influence of the PDA linker.
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(This article belongs to the Special Issue Silk-Based Functional Materials: New Ways of Production, Properties and Applications)
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Open AccessReview
Development of Personalized Strategies for Precisely Battling Malignant Melanoma
by
Armond J. Isaak, GeGe R. Clements, Rand Gabriel M. Buenaventura, Glenn Merlino and Yanlin Yu
Int. J. Mol. Sci. 2024, 25(9), 5023; https://doi.org/10.3390/ijms25095023 (registering DOI) - 04 May 2024
Abstract
Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor and inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond the ability for surgical resection rely on currently accepted standard therapies,
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Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor and inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond the ability for surgical resection rely on currently accepted standard therapies, notably immune checkpoint inhibitors and targeted therapies. Acquired resistance to these therapies and treatment-associated toxicity necessitate exploring novel strategies, especially those that can be personalized for specific patients and/or populations. Here, we review the current landscape and progress of standard therapies and explore what personalized oncology techniques may entail in the scope of melanoma. Our purpose is to provide an up-to-date summary of the tools at our disposal that work to circumvent the common barriers faced when battling melanoma.
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(This article belongs to the Special Issue Melanoma: From Molecular Pathology to Therapeutic Approaches)
Open AccessArticle
Gelatin Enhances the Wet Mechanical Properties of Poly(D,L-Lactic Acid) Membranes
by
Deuk Yong Lee
Int. J. Mol. Sci. 2024, 25(9), 5022; https://doi.org/10.3390/ijms25095022 (registering DOI) - 04 May 2024
Abstract
Biodegradable (BP) poly(D,L-lactic acid) (PDLLA) membranes are widely used in tissue engineering. Here, we investigate the effects of varying concentrations of PDLLA/gelatin membranes electrospun in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; C3H2F6O) solvent on their mechanical and physical properties as well
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Biodegradable (BP) poly(D,L-lactic acid) (PDLLA) membranes are widely used in tissue engineering. Here, we investigate the effects of varying concentrations of PDLLA/gelatin membranes electrospun in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; C3H2F6O) solvent on their mechanical and physical properties as well as their biocompatibility. Regardless of the environmental conditions, increasing the gelatin content resulted in elevated stress and reduced strain at membrane failure. There was a remarkable difference in strain-to-failure between dry and wet PDLLA/gelatin membranes, with wet strains consistently higher than those of the dry membranes because of the hydrophilic nature of gelatin. A similar wet strain (εw = 2.7–3.0) was observed in PDLLA/gelatin membranes with a gelatin content between 10 and 40%. Both dry and wet stresses increased with increasing gelatin content. The dry stress on PDLLA/gelatin membranes (σd = 6.7–9.7 MPa) consistently exceeded the wet stress (σw = 4.5–8.6 MPa). The water uptake capacity (WUC) improved, increasing from 57% to 624% with the addition of 40% gelatin to PDLLA. PDLLA/gelatin hybrid membranes containing 10 to 20 wt% gelatin exhibited favorable wet mechanical properties (σw = 5.4–6.3 MPa; εw = 2.9–3.0); WUC (337–571%), degradability (11.4–20.2%), and excellent biocompatibility.
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(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration 3.0)
Open AccessArticle
Nontraditional Roles of Magnesium Ions in Modulating Sav2152: Insight from a Haloacid Dehalogenase-like Superfamily Phosphatase from Staphylococcus aureus
by
Jaeseok Bang, Jaehui Park, Sung-Hee Lee, Jinhwa Jang, Junwoo Hwang, Otabek Kamarov, Hae-Joon Park, Soo-Jae Lee, Min-Duk Seo, Hyung-Sik Won, Seung-Hyeon Seok and Ji-Hun Kim
Int. J. Mol. Sci. 2024, 25(9), 5021; https://doi.org/10.3390/ijms25095021 (registering DOI) - 04 May 2024
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infection has rapidly spread through various routes. A genomic analysis of clinical MRSA samples revealed an unknown protein, Sav2152, predicted to be a haloacid dehalogenase (HAD)-like hydrolase, making it a potential candidate for a novel drug target. In this
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Methicillin-resistant Staphylococcus aureus (MRSA) infection has rapidly spread through various routes. A genomic analysis of clinical MRSA samples revealed an unknown protein, Sav2152, predicted to be a haloacid dehalogenase (HAD)-like hydrolase, making it a potential candidate for a novel drug target. In this study, we determined the crystal structure of Sav2152, which consists of a C2-type cap domain and a core domain. The core domain contains four motifs involved in phosphatase activity that depend on the presence of Mg2+ ions. Specifically, residues D10, D12, and D233, which closely correspond to key residues in structurally homolog proteins, are responsible for binding to the metal ion and are known to play critical roles in phosphatase activity. Our findings indicate that the Mg2+ ion known to stabilize local regions surrounding it, however, paradoxically, destabilizes the local region. Through mutant screening, we identified D10 and D12 as crucial residues for metal binding and maintaining structural stability via various uncharacterized intra-protein interactions, respectively. Substituting D10 with Ala effectively prevents the interaction with Mg2+ ions. The mutation of D12 disrupts important structural associations mediated by D12, leading to a decrease in the stability of Sav2152 and an enhancement in binding affinity to Mg2+ ions. Additionally, our study revealed that D237 can replace D12 and retain phosphatase activity. In summary, our work uncovers the novel role of metal ions in HAD-like phosphatase activity.
Full article
(This article belongs to the Special Issue Mechanism of Enzyme Catalysis: When Structure Meets Function)
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An Overview on Atopic Dermatitis, Oxidative Stress, and Psychological Stress: Possible Role of Nutraceuticals as an Additional Therapeutic Strategy
by
Clara Alessandrello, Serena Sanfilippo, Paola L. Minciullo and Sebastiano Gangemi
Int. J. Mol. Sci. 2024, 25(9), 5020; https://doi.org/10.3390/ijms25095020 (registering DOI) - 04 May 2024
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin condition with a considerable impact on patients’ quality of life. Its etiology is multifactorial and, among the predisposing factors, a role is played by oxidative stress. Pollution, recurrent infections, and psychological stress contribute to oxidative
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Atopic dermatitis (AD) is a chronic inflammatory skin condition with a considerable impact on patients’ quality of life. Its etiology is multifactorial and, among the predisposing factors, a role is played by oxidative stress. Pollution, recurrent infections, and psychological stress contribute to oxidative stress, amplifying the production of proinflammatory cytokines and worsening barrier damage. There are various oxidative stress mechanisms involved in the pathogenesis of AD. Moreover, AD often appears to be associated with psychological disorders such as alexithymia, depression, and anxiety due to severe itching and related insomnia, as well as social distress and isolation. The increasing incidence of AD requires the evaluation of additional therapeutic approaches in order to reduce the psychological burden of this condition. Our review aims to evaluate the role of some nutraceuticals in AD treatment and its related psychological comorbidities. The combination of some natural compounds (flavonoids, alkaloids, terpenes, isothiocyanates) with traditional AD treatments might be useful in improving the effectiveness of therapy, by reducing chronic inflammation and preventing flare-ups, and in promoting corticosteroid sparing. In addition, some of these nutraceuticals also appear to have a role in the treatment of psychological disorders, although the underlying oxidative stress mechanisms are different from those already known for AD.
Full article
(This article belongs to the Special Issue Valuable Bioactive Compounds from Prokaryotic and Eukaryotic Organisms)
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The Transcription Factor Mohawk Facilitates Skeletal Muscle Repair via Modulation of the Inflammatory Environment
by
Cherie Alissa Lynch, Sofia A. Acosta, Douglas M. Anderson, Gavin E. Rogers, Jeanne Wilson-Rawls and Alan Rawls
Int. J. Mol. Sci. 2024, 25(9), 5019; https://doi.org/10.3390/ijms25095019 (registering DOI) - 04 May 2024
Abstract
Efficient repair of skeletal muscle relies upon the precise coordination of cells between the satellite cell niche and innate immune cells that are recruited to the site of injury. The expression of pro-inflammatory cytokines and chemokines such as TNFα, IFNγ, CXCL1, and CCL2,
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Efficient repair of skeletal muscle relies upon the precise coordination of cells between the satellite cell niche and innate immune cells that are recruited to the site of injury. The expression of pro-inflammatory cytokines and chemokines such as TNFα, IFNγ, CXCL1, and CCL2, by muscle and tissue resident immune cells recruits neutrophils and M1 macrophages to the injury and activates satellite cells. These signal cascades lead to highly integrated temporal and spatial control of muscle repair. Despite the therapeutic potential of these factors for improving tissue regeneration after traumatic and chronic injuries, their transcriptional regulation is not well understood. The transcription factor Mohawk (Mkx) functions as a repressor of myogenic differentiation and regulates fiber type specification. Embryonically, Mkx is expressed in all progenitor cells of the musculoskeletal system and is expressed in human and mouse myeloid lineage cells. An analysis of mice deficient for Mkx revealed a delay in postnatal muscle repair characterized by impaired clearance of necrotic fibers and smaller newly regenerated fibers. Further, there was a delay in the expression of inflammatory signals such as Ccl2, Ifnγ, and Tgfß. This was coupled with impaired recruitment of pro-inflammatory macrophages to the site of muscle damage. These studies demonstrate that Mkx plays a critical role in adult skeletal muscle repair that is mediated through the initial activation of the inflammatory response.
Full article
(This article belongs to the Special Issue Research on Skeletal and Cardiac Muscle Regeneration Mechanisms)
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