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
Multiple Sclerosis: From the Application of Oligoclonal Bands to Novel Potential Biomarkers
Int. J. Mol. Sci. 2024, 25(10), 5412; https://doi.org/10.3390/ijms25105412 (registering DOI) - 15 May 2024
Abstract
Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system with a high heterogeneity among patients. In the clinical setting, one of the main challenges is a proper and early diagnosis for the prediction of disease activity. Current diagnosis is based
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Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system with a high heterogeneity among patients. In the clinical setting, one of the main challenges is a proper and early diagnosis for the prediction of disease activity. Current diagnosis is based on the integration of clinical, imaging, and laboratory results, with the latter based on the presence of intrathecal IgG oligoclonal bands in the cerebrospinal fluid whose detection via isoelectric focusing followed by immunoblotting represents the gold standard. Intrathecal synthesis can also be evidenced by the measurement of kappa free light chains in the cerebrospinal fluid, which has reached similar diagnostic accuracy compared to that of oligoclonal bands in the identification of patients with multiple sclerosis; moreover, recent studies have also highlighted its value for early disease activity prediction. This strategy has significant advantages as compared to using oligoclonal band detection, even though some issues remain open. Here, we discuss the current methods applied for cerebrospinal fluid analysis to achieve the most accurate diagnosis and for follow-up and prognosis evaluation. In addition, we describe new promising biomarkers, currently under investigation, that could contribute both to a better diagnosis of multiple sclerosis and to its monitoring of the therapeutic treatment response.
Full article
(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology)
Open AccessArticle
Highlighting the Major Role of Cyclin C in Cyclin-Dependent Kinase 8 Activity through Molecular Dynamics Simulations
by
Sonia Ziada, Julien Diharce, Dylan Serillon, Pascal Bonnet and Samia Aci-Sèche
Int. J. Mol. Sci. 2024, 25(10), 5411; https://doi.org/10.3390/ijms25105411 (registering DOI) - 15 May 2024
Abstract
Dysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family
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Dysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family members are generally activated in two steps, that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated with CycC while adopting an inactive form. These specificities raise the question of the role of CycC in the complex CDK8–CycC, which appears to be more complex than the other members of the CDK family. Through molecular dynamics (MD) simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8. In a second step, we particularly focused our investigation on the structural and molecular basis of the protein–protein interaction between the two partners by finely analyzing the energetic contribution of residues and simulating the transition between the active and the inactive form. We found that CycC has a stabilizing effect on CDK8, and we identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of CycC is involved in the orientation of three conserved arginines of CDK8. Thus, this residue may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point to the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.
Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations and Structural Analysis of Protein Domains)
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Open AccessArticle
Analyzing the Functional Roles and Immunological Features of Chemokines in COAD
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Houxi Xu and Yihua Song
Int. J. Mol. Sci. 2024, 25(10), 5410; https://doi.org/10.3390/ijms25105410 (registering DOI) - 15 May 2024
Abstract
Chemokines are key proteins that regulate cell migration and immune responses and are essential for modulating the tumor microenvironment. Despite their close association with colon cancer, the expression patterns, prognosis, immunity, and specific roles of chemokines in colon cancer are still not fully
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Chemokines are key proteins that regulate cell migration and immune responses and are essential for modulating the tumor microenvironment. Despite their close association with colon cancer, the expression patterns, prognosis, immunity, and specific roles of chemokines in colon cancer are still not fully understood. In this study, we investigated the mutational features, differential expression, and immunological characteristics of chemokines in colon cancer (COAD) by analyzing the Tumor Genome Atlas (TCGA) database. We clarified the biological functions of these chemokines using Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. By univariate and multivariate COX regression analyses, we developed chemokine-based prognostic risk models. In addition, using Gene Set Enrichment Analysis (GSEA) and Gene Set Variant Analysis (GSVA), we analyzed the differences in immune responses and signaling pathways among different risk groups. The results showed that the mutation rate of chemokines was low in COAD, but 25 chemokines were significantly differentially expressed. These chemokines function in several immune-related biological processes and play key roles in signaling pathways including cytokine–cytokine receptor interactions, NF-kappa B, and IL-17. Prognostic risk models based on CCL22, CXCL1, CXCL8, CXCL9, and CXCL11 performed well. GSEA and GSVA analyses showed significant differences in immune responses and signaling pathways across risk groups. In conclusion, this study reveals the potential molecular mechanisms of chemokines in COAD and proposes a new prognostic risk model based on these insights.
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(This article belongs to the Topic Advances in Colorectal Cancer Therapy)
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Open AccessArticle
Association of Glutathione Peroxidase 3 (GPx3) and miR-196a with Carbohydrate Metabolism Disorders in the Elderly
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Adam Włodarski, Izabela Szymczak-Pajor, Jacek Kasznicki, Egle Morta Antanaviciute, Bożena Szymańska and Agnieszka Śliwińska
Int. J. Mol. Sci. 2024, 25(10), 5409; https://doi.org/10.3390/ijms25105409 (registering DOI) - 15 May 2024
Abstract
The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS)
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The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS) and oxidative stress (OxS). This condition, resulting from chronic hyperglycemia and insufficient antioxidant defense, causes damage to biomolecules, triggering diabetes complications. Additionally, aging itself can serve as a source of OxS due to the weakening of antioxidant defense mechanisms. Notably, previous research indicates that miR-196a, by downregulating glutathione peroxidase 3 (GPx3), contributes to insulin resistance (IR). Additionally, a GPx3 decrease is observed in overweight/obese and insulin-resistant individuals and in the elderly population. This study investigates plasma GPx3 levels and miR-196a expression as potential CMD risk indicators. We used ELISA to measure GPx3 and qRT-PCR for miR-196a expression, supplemented by multivariate linear regression and receiver operating characteristic (ROC) analysis. Our findings included a significant GPx3 reduction in the CMD patients (n = 126), especially in the T2DM patients (n = 51), and a decreasing trend in the prediabetes group (n = 37). miR-196a expression, although higher in the CMD and T2DM groups than in the controls, was not statistically significant, potentially due to the small sample size. In the individuals with CMD, GPx3 levels exhibited a negative correlation with the mass of adipose tissue, muscle, and total body water, while miR-196a positively correlated with fat mass. In the CMD group, the analysis revealed a weak negative correlation between glucose and GPx3 levels. ROC analysis indicated a 5.2-fold increased CMD risk with GPx3 below 419.501 ng/mL. Logistic regression suggested that each 100 ng/mL GPx3 increase corresponded to a roughly 20% lower CMD risk (OR = 0.998; 95% CI: 0.996–0.999; p = 0.031). These results support the potential of GPx3 as a biomarker for CMD, particularly in T2DM, and the lack of a significant decline in GPx3 levels in prediabetic individuals suggests that it may not serve reliably as an early indicator of CMDs, warranting further large-scale validation.
Full article
(This article belongs to the Special Issue Current Research on Diabetes and Metabolic Syndrome)
Open AccessReview
Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer
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Julius Gretschel, Racha El Hage, Ruirui Wang, Yifang Chen, Anne Pietzner, Andreas Loew, Can G. Leineweber, Jonas Wördemann, Nadine Rohwer, Karsten H. Weylandt and Christoph Schmöcker
Int. J. Mol. Sci. 2024, 25(10), 5408; https://doi.org/10.3390/ijms25105408 (registering DOI) - 15 May 2024
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence
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Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (n − 6) PUFAs and low levels of omega-3 (n − 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of n − 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics.
Full article
(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases 2.0)
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Open AccessEditorial
Latest Review Papers in Molecular Plant Sciences 2023
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Setsuko Komatsu and Andrei Smertenko
Int. J. Mol. Sci. 2024, 25(10), 5407; https://doi.org/10.3390/ijms25105407 - 15 May 2024
Abstract
Success in sustaining food security in the face of global climate change depends on the multi-disciplinary efforts of plant science, physics, mathematics, and computer sciences, whereby each discipline contributes specific concepts, information, and tools [...]
Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Plant Sciences 2023)
Open AccessArticle
Integrating Genome-Scale Metabolic Models with Patient Plasma Metabolome to Study Endothelial Metabolism In Situ
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Fernando Silva-Lance, Isabel Montejano-Montelongo, Eric Bautista, Lars K. Nielsen, Pär I. Johansson and Igor Marin de Mas
Int. J. Mol. Sci. 2024, 25(10), 5406; https://doi.org/10.3390/ijms25105406 - 15 May 2024
Abstract
Patient blood samples are invaluable in clinical omics databases, yet current methodologies often fail to fully uncover the molecular mechanisms driving patient pathology. While genome-scale metabolic models (GEMs) show promise in systems medicine by integrating various omics data, having only exometabolomic data remains
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Patient blood samples are invaluable in clinical omics databases, yet current methodologies often fail to fully uncover the molecular mechanisms driving patient pathology. While genome-scale metabolic models (GEMs) show promise in systems medicine by integrating various omics data, having only exometabolomic data remains a limiting factor. To address this gap, we introduce a comprehensive pipeline integrating GEMs with patient plasma metabolome. This pipeline constructs case-specific GEMs using literature-based and patient-specific metabolomic data. Novel computational methods, including adaptive sampling and an in-house developed algorithm for the rational exploration of the sampled space of solutions, enhance integration accuracy while improving computational performance. Model characterization involves task analysis in combination with clustering methods to identify critical cellular functions. The new pipeline was applied to a cohort of trauma patients to investigate shock-induced endotheliopathy using patient plasma metabolome data. By analyzing endothelial cell metabolism comprehensively, the pipeline identified critical therapeutic targets and biomarkers that can potentially contribute to the development of therapeutic strategies. Our study demonstrates the efficacy of integrating patient plasma metabolome data into computational models to analyze endothelial cell metabolism in disease contexts. This approach offers a deeper understanding of metabolic dysregulations and provides insights into diseases with metabolic components and potential treatments.
Full article
(This article belongs to the Special Issue Bioinformatics Study in Human Diseases: Integration of Omics Data for Personalized Medicine)
Open AccessArticle
Two Enterococcus faecium Isolates Demonstrated Modulating Effects on the Dysbiosis of Mice Gut Microbiota Induced by Antibiotic Treatment
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Xiaohui Yao, Wansen Nie, Xi Chen, Junjie Zhang, Jianchao Wei, Yafeng Qiu, Ke Liu, Donghua Shao, Haixia Liu, Zhiyong Ma, Zongjie Li and Beibei Li
Int. J. Mol. Sci. 2024, 25(10), 5405; https://doi.org/10.3390/ijms25105405 - 15 May 2024
Abstract
Broad-spectrum antibiotics are frequently used to treat bacteria-induced infections, but the overuse of antibiotics may induce the gut microbiota dysbiosis and disrupt gastrointestinal tract function. Probiotics can be applied to restore disturbed gut microbiota and repair abnormal intestinal metabolism. In the present study,
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Broad-spectrum antibiotics are frequently used to treat bacteria-induced infections, but the overuse of antibiotics may induce the gut microbiota dysbiosis and disrupt gastrointestinal tract function. Probiotics can be applied to restore disturbed gut microbiota and repair abnormal intestinal metabolism. In the present study, two strains of Enterococcus faecium (named DC-K7 and DC-K9) were isolated and characterized from the fecal samples of infant dogs. The genomic features of E. faecium DC-K7 and DC-K9 were analyzed, the carbohydrate-active enzyme (CAZyme)-encoding genes were predicted, and their abilities to produce short-chain fatty acids (SCFAs) were investigated. The bacteriocin-encoding genes in the genome sequences of E. faecium DC-K7 and DC-K9 were analyzed, and the gene cluster of Enterolysin-A, which encoded a 401-amino-acid peptide, was predicted. Moreover, the modulating effects of E. faecium DC-K7 and DC-K9 on the gut microbiota dysbiosis induced by antibiotics were analyzed. The current results demonstrated that oral administrations of E. faecium DC-K7 and DC-K9 could enhance the relative abundances of beneficial microbes and decrease the relative abundances of harmful microbes. Therefore, the isolated E. faecium DC-K7 and DC-K9 were proven to be able to alter the gut microbiota dysbiosis induced by antibiotic treatment.
Full article
(This article belongs to the Topic Microbes and Their Products for Sustainable Human Life)
Open AccessArticle
In Vitro Digestion of Polyphenolic Compounds and the Antioxidant Activity of Acorn Flour and Pasta Enriched with Acorn Flour
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Kamila Kasprzak-Drozd, Jarosław Mołdoch, Marek Gancarz, Agnieszka Wójtowicz, Iwona Kowalska, Tomasz Oniszczuk and Anna Oniszczuk
Int. J. Mol. Sci. 2024, 25(10), 5404; https://doi.org/10.3390/ijms25105404 - 15 May 2024
Abstract
Acorn flour is a rich source of nutrients and is beneficial to human health due to, among other things, its low glycemic index and polyphenol content. In order to obtain more accurate data on the levels and activities of the substances tested after
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Acorn flour is a rich source of nutrients and is beneficial to human health due to, among other things, its low glycemic index and polyphenol content. In order to obtain more accurate data on the levels and activities of the substances tested after ingestion and digestion, it may be beneficial to use a simulated in vitro digestion method. Therefore, the objective of the present study was to elucidate the content of polyphenols, individual phenolic acids, flavonoids and antiradical properties of acorn flour and pasta enriched with acorn flour before and after simulated in vitro gastrointestinal digestion. The results indicate that the total polyphenol content (TPC), flavonoid content and radical scavenging activity exhibited an increasing trend following the initial digestion stage and a decreasing trend following the second stage. Nevertheless, the levels of phenolic acids demonstrated an increase in both digestion phases. The digestion processes of polyphenols in acorn flour differ significantly from those in pasta. In the case of pasta, total polyphenols , phenolic acids and flavonoids, as well as free radical scavenging properties, demonstrated a decreasing trend following each digestion stage.
Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
Open AccessArticle
BMPR2 Loss Activates AKT by Disrupting DLL4/NOTCH1 and PPARγ Signaling in Pulmonary Arterial Hypertension
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Keytam S. Awad, Shuibang Wang, Edward J. Dougherty, Ali Keshavarz, Cumhur Y. Demirkale, Zu Xi Yu, Latonia Miller, Jason M. Elinoff and Robert L. Danner
Int. J. Mol. Sci. 2024, 25(10), 5403; https://doi.org/10.3390/ijms25105403 - 15 May 2024
Abstract
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by pathologic vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane
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Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by pathologic vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in pulmonary artery endothelial cells (PAECs) activated AKT and suppressed the expression of DLL4. Consistent with these in vitro findings, increased AKT activation and reduced DLL4 expression was found in the small pulmonary arteries of patients with PAH. Increased NOTCH1 activation through exogenous DLL4 blocked AKT activation, decreased proliferation and reversed EndoMT. Exogenous and overexpression of DLL4 induced BMPR2 and PPRE promoter activity, and BMPR2 and PPARG mRNA in idiopathic PAH (IPAH) ECs. PPARγ, a nuclear receptor associated with EC homeostasis, suppressed by BMPR2 loss was induced and activated by DLL4/NOTCH1 signaling in both BMPR2-silenced and IPAH ECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Directly blocking AKT or restoring DLL4/NOTCH1/PPARγ signaling may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.
Full article
(This article belongs to the Special Issue Activation, Proliferation and Migration of Endothelial Cells under Normal and Pathological Conditions)
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Open AccessArticle
Functional Analysis of the Major Pilin Proteins of Type IV Pili in Streptococcus sanguinis CGMH010
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Yi-Ywan M. Chen, Yuan-Chen Yang, Hui-Ru Shieh, Yu-Juan Lin, Wan-Ju Ke and Cheng-Hsun Chiu
Int. J. Mol. Sci. 2024, 25(10), 5402; https://doi.org/10.3390/ijms25105402 - 15 May 2024
Abstract
The pil gene cluster for Type IV pilus (Tfp) biosynthesis is commonly present and highly conserved in Streptococcus sanguinis. Nevertheless, Tfp-mediated twitching motility is less common among strains, and the factors determining twitching activity are not fully understood. Here, we analyzed the
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The pil gene cluster for Type IV pilus (Tfp) biosynthesis is commonly present and highly conserved in Streptococcus sanguinis. Nevertheless, Tfp-mediated twitching motility is less common among strains, and the factors determining twitching activity are not fully understood. Here, we analyzed the functions of three major pilin proteins (PilA1, PilA2, and PilA3) in the assembly and activity of Tfp in motile S. sanguinis CGMH010. Using various recombinant pilA deletion strains, we found that Tfp composed of different PilA proteins varied morphologically and functionally. Among the three PilA proteins, PilA1 was most critical in the assembly of twitching-active Tfp, and recombinant strains expressing motility generated more structured biofilms under constant shearing forces compared to the non-motile recombinant strains. Although PilA1 and PilA3 shared 94% identity, PilA3 could not compensate for the loss of PilA1, suggesting that the nature of PilA proteins plays an essential role in twitching activity. The single deletion of individual pilA genes had little effect on the invasion of host endothelia by S. sanguinis CGMH010. In contrast, the deletion of all three pilA genes or pilT, encoding the retraction ATPase, abolished Tfp-mediated invasion. Tfp- and PilT-dependent invasion were also detected in the non-motile S. sanguinis SK36, and thus, the retraction of Tfp, but not active twitching, was found to be essential for invasion.
Full article
(This article belongs to the Section Molecular Microbiology)
Open AccessArticle
In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice
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Susanne Paukner, Sandra Kimber, Charlotte Cumper, Tina Rea-Davies, Lorena Sueiro Ballesteros, Christopher Kirkham, Adam Hargreaves, Steven P. Gelone, Claire Richards and Wolfgang W. Wicha
Int. J. Mol. Sci. 2024, 25(10), 5401; https://doi.org/10.3390/ijms25105401 - 15 May 2024
Abstract
Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical
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Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant ‘low’ dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
Full article
(This article belongs to the Section Molecular Biology)
Open AccessArticle
ADPN Regulates Oxidative Stress-Induced Follicular Atresia in Geese by Modulating Granulosa Cell Apoptosis and Autophagy
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Yan Zheng, Yunqiao Qiu, Qianhui Wang, Ming Gao, Zhongzan Cao and Xinhong Luan
Int. J. Mol. Sci. 2024, 25(10), 5400; https://doi.org/10.3390/ijms25105400 - 15 May 2024
Abstract
Geese are susceptible to oxidative stress during reproduction, which can lead to follicular atresia and impact egg production. Follicular atresia is directly triggered by the apoptosis and autophagy of granulosa cells (GCs). Adiponectin (ADPN), which is secreted by adipose tissue, has good antioxidant
[...] Read more.
Geese are susceptible to oxidative stress during reproduction, which can lead to follicular atresia and impact egg production. Follicular atresia is directly triggered by the apoptosis and autophagy of granulosa cells (GCs). Adiponectin (ADPN), which is secreted by adipose tissue, has good antioxidant and anti-apoptotic capacity, but its role in regulating the apoptosis of GCs in geese is unclear. To investigate this, this study examined the levels of oxidative stress, apoptosis, and autophagy in follicular tissues and GCs using RT-qPCR, Western blotting, immunofluorescence, flow cytometry, transcriptomics and other methods. Atretic follicles exhibited high levels of oxidative stress and apoptosis, and autophagic flux was obstructed. Stimulating GCs with H2O2 produced results similar to those of atretic follicles. The effects of ADPN overexpression and knockdown on oxidative stress, apoptosis and autophagy in GCs were investigated. ADPN was found to modulate autophagy and reduced oxidative stress and apoptosis in GCs, in addition to protecting them from H2O2-induced damage. These results may provide a reasonable reference for improving egg-laying performance of geese.
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(This article belongs to the Section Molecular Biology)
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Open AccessReview
The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis
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Maja Mizdrak, Tina Ticinovic Kurir, Ivan Mizdrak, Marko Kumric, Mladen Krnic and Josko Bozic
Int. J. Mol. Sci. 2024, 25(10), 5399; https://doi.org/10.3390/ijms25105399 - 15 May 2024
Abstract
Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible
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Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.
Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
Open AccessArticle
Protopine and Allocryptopine Interactions with Plasma Proteins
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Aleksandra Marciniak, Aleksandra Kotynia, Edward Krzyżak, Żaneta Czyżnikowska, Sylwia Zielińska, Weronika Kozłowska, Marcel Białas, Adam Matkowski and Anna Jezierska-Domaradzka
Int. J. Mol. Sci. 2024, 25(10), 5398; https://doi.org/10.3390/ijms25105398 - 15 May 2024
Abstract
A comprehensive study of the interactions of human serum albumin (HSA) and α-1-acid glycoprotein (AAG) with two isoquinoline alkaloids, i.e., allocryptopine (ACP) and protopine (PP), was performed. The UV-Vis spectroscopy, molecular docking, competitive binding assays, and circular dichroism (CD) spectroscopy were used for
[...] Read more.
A comprehensive study of the interactions of human serum albumin (HSA) and α-1-acid glycoprotein (AAG) with two isoquinoline alkaloids, i.e., allocryptopine (ACP) and protopine (PP), was performed. The UV-Vis spectroscopy, molecular docking, competitive binding assays, and circular dichroism (CD) spectroscopy were used for the investigations. The results showed that ACP and PP form spontaneous and stable complexes with HSA and AAG, with ACP displaying a stronger affinity towards both proteins. Molecular docking studies revealed the preferential binding of ACP and PP to specific sites within HSA, with site 2 (IIIA) being identified as the favored location for both alkaloids. This was supported by competitive binding assays using markers specific to HSA’s drug binding sites. Similarly, for AAG, a decrease in fluorescence intensity upon addition of the alkaloids to AAG/quinaldine red (QR) complexes indicated the replacement of the marker by the alkaloids, with ACP showing a greater extent of replacement than PP. CD spectroscopy showed that the proteins’ structures remained largely unchanged, suggesting that the formation of complexes did not significantly perturb the overall spatial configuration of these macromolecules. These findings are crucial for advancing the knowledge on the natural product–protein interactions and the future design of isoquinoline alkaloid-based therapeutics.
Full article
(This article belongs to the Special Issue Investigation of Natural Products as Sources of Bioactive Molecules)
Open AccessReview
Multiplicative Effects of Essential Oils and Other Active Components on Skin Tissue and Skin Cancers
by
Hyeong Jae Kim and Jeong Hee Hong
Int. J. Mol. Sci. 2024, 25(10), 5397; https://doi.org/10.3390/ijms25105397 - 15 May 2024
Abstract
Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various
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Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.
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(This article belongs to the Special Issue Current Research in Antimicrobial Natural Products)
Open AccessArticle
Metabolic Composition of Methanolic Extract of the Balkan Endemic Species Micromeria frivaldszkyana (Degen) Velen and Its Anti-Inflammatory Effect on Male Wistar Rats
by
Kristina Stavrakeva, Kalina Metodieva, Maria Benina, Anelia Bivolarska, Ivica Dimov, Mariya Choneva, Vesela Kokova, Saleh Alseekh, Valentina Ivanova, Emil Vatov, Tsanko Gechev, Tsvetelina Mladenova, Rumen Mladenov, Krasimir Todorov, Plamen Stoyanov, Donika Gyuzeleva, Mihaela Popova and Elisaveta Apostolova
Int. J. Mol. Sci. 2024, 25(10), 5396; https://doi.org/10.3390/ijms25105396 - 15 May 2024
Abstract
Extracts from medicinal plants are widely used in the treatment and prevention of different diseases. Micromeria frivaldszkyana is a Balkan endemic species with reported antioxidant and antimicrobial characteristics; however, its phytochemical composition is not well defined. Here, we examined the metabolome of M.
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Extracts from medicinal plants are widely used in the treatment and prevention of different diseases. Micromeria frivaldszkyana is a Balkan endemic species with reported antioxidant and antimicrobial characteristics; however, its phytochemical composition is not well defined. Here, we examined the metabolome of M. frivaldszkyana by chromatography–mass spectrometry (GC-MS), ultra-performance liquid chromatography–mass spectrometry (UPLC-MS-MS), and inductively coupled plasma mass spectrometry (ICP-MS). Amino acids, organic acids, sugars, and sugar alcohols were the primary metabolites with the highest levels in the plant extract. Detailed analysis of the sugar content identified high levels of sucrose, glucose, mannose, and fructose. Lipids are primary plant metabolites, and the analysis revealed triacylglycerols as the most abundant lipid group. Potassium (K), magnesium (Mg), zinc (Zn), and calcium (Ca) were the elements with the highest content. The results showed linarin, 3-caffeoil-quinic acid, and rosmarinic acid, as well as a number of polyphenols, as the most abundant secondary metabolites. Among the flavonoids and polyphenols with a high presence were eupatorin, kaempferol, and apigenin—compounds widely known for their bioactive properties. Further, the acute toxicity and potential anti-inflammatory activity of the methanolic extract were evaluated in Wistar rats. No toxic effects were registered after a single oral application of the extract in doses of between 200 and 5000 mg/kg bw. A fourteen-day pre-treatment with methanolic extract of M. frivaldszkyana in doses of 250, 400, and 500 mg/kg bw induced anti-inflammatory activity in the 1st, 2nd, and 3rd hours after carrageenan injection in a model of rat paw edema. This effect was also present in the 4th hour only in the group treated with a dose of 500 mg/kg. In conclusion, M. frivaldszkyana extract is particularly rich in linarin, rosmarinic acid, and flavonoids (eupatorin, kaempferol, and apigenin). Its methanolic extract induced no toxicity in male Wistar rats after oral application in doses of up to 5000 mg/kg bw. Additionally, treatment with the methanolic extract for 14 days revealed anti-inflammatory potential in a model of rat paw edema on the 1st, 2nd, and 3rd hours after the carrageenan injection. These results show the anti-inflammatory potential of the plant, which might be considered for further exploration and eventual application as a phytotherapeutic agent.
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(This article belongs to the Special Issue Functions and Applications of Natural Products)
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Open AccessReview
Promising Role of Alkaloids in the Prevention and Treatment of Thyroid Cancer and Autoimmune Thyroid Disease: A Comprehensive Review of the Current Evidence
by
Giulia Di Dalmazi, Cesidio Giuliani, Ines Bucci, Marco Mascitti and Giorgio Napolitano
Int. J. Mol. Sci. 2024, 25(10), 5395; https://doi.org/10.3390/ijms25105395 - 15 May 2024
Abstract
Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD
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Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD as a risk factor for TC, although this issue remains controversial. Prevention of autoimmune disease and cancer is the ultimate goal for clinicians and scientists, but it is not always feasible. Thus, new treatments, that overcome the current barriers to prevention and treatment of TC and AITD are needed. Alkaloids are secondary plant metabolites endowed with several biological activities including anticancer and immunomodulatory properties. In this perspective, alkaloids may represent a promising source of prophylactic and therapeutic agents for TC and AITD. This review encompasses the current published literature on alkaloids effects on TC and AITD, with a specific focus on the pathways involved in TC and AITD development and progression.
Full article
(This article belongs to the Special Issue Thyroid Disorders and Cancers: Molecular Mechanisms and Advanced Therapies)
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Open AccessReview
Speeding up Glioblastoma Cancer Research: Highlighting the Zebrafish Xenograft Model
by
Giusi Alberti, Maria Denise Amico, Celeste Caruso Bavisotto, Francesca Rappa, Antonella Marino Gammazza, Fabio Bucchieri, Francesco Cappello, Federica Scalia and Marta Anna Szychlinska
Int. J. Mol. Sci. 2024, 25(10), 5394; https://doi.org/10.3390/ijms25105394 - 15 May 2024
Abstract
Glioblastoma multiforme (GBM) is a very aggressive and lethal primary brain cancer in adults. The multifaceted nature of GBM pathogenesis, rising from complex interactions between cells and the tumor microenvironment (TME), has posed great treatment challenges. Despite significant scientific efforts, the prognosis for
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Glioblastoma multiforme (GBM) is a very aggressive and lethal primary brain cancer in adults. The multifaceted nature of GBM pathogenesis, rising from complex interactions between cells and the tumor microenvironment (TME), has posed great treatment challenges. Despite significant scientific efforts, the prognosis for GBM remains very poor, even after intensive treatment with surgery, radiation, and chemotherapy. Efficient GBM management still requires the invention of innovative treatment strategies. There is a strong necessity to complete cancer in vitro studies and in vivo studies to properly evaluate the mechanisms of tumor progression within the complex TME. In recent years, the animal models used to study GBM tumors have evolved, achieving highly invasive GBM models able to provide key information on the molecular mechanisms of GBM onset. At present, the most commonly used animal models in GBM research are represented by mammalian models, such as mouse and canine ones. However, the latter present several limitations, such as high cost and time-consuming management, making them inappropriate for large-scale anticancer drug evaluation. In recent years, the zebrafish (Danio rerio) model has emerged as a valuable tool for studying GBM. It has shown great promise in preclinical studies due to numerous advantages, such as its small size, its ability to generate a large cohort of genetically identical offspring, and its rapid development, permitting more time- and cost-effective management and high-throughput drug screening when compared to mammalian models. Moreover, due to its transparent nature in early developmental stages and genetic and anatomical similarities with humans, it allows for translatable brain cancer research and related genetic screening and drug discovery. For this reason, the aim of the present review is to highlight the potential of relevant transgenic and xenograft zebrafish models and to compare them to the traditionally used animal models in GBM research.
Full article
(This article belongs to the Special Issue The Zebrafish Model in Animal and Human Health Research)
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Open AccessArticle
Effect of Curcumin on Hepatic mRNA and lncRNA Co-Expression in Heat-Stressed Laying Hens
by
Xinyue Wu, Xubin Du, Huifang Pian and Debing Yu
Int. J. Mol. Sci. 2024, 25(10), 5393; https://doi.org/10.3390/ijms25105393 - 15 May 2024
Abstract
Heat stress is an important factor affecting poultry production; birds have a range of inflammatory reactions under high-temperature environments. Curcumin has anti-inflammatory and antioxidant effects. The purpose of this experiment was to investigate the effect of dietary curcumin supplementation on the liver transcriptome
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Heat stress is an important factor affecting poultry production; birds have a range of inflammatory reactions under high-temperature environments. Curcumin has anti-inflammatory and antioxidant effects. The purpose of this experiment was to investigate the effect of dietary curcumin supplementation on the liver transcriptome of laying hens under heat stress conditions. In the animal experiment, a total of 240 Hy-Line brown hens aged 280 days were divided randomly into four different experimental diets with four replicates, and each replicate consisted of 15 hens during a 42-D experiment. The ambient temperature was adjusted to 34 ± 2 °C for 8 h per day, transiting to a range of 22 °C to 28 °C for the remaining 16 h. In the previous study of our lab, it was found that supplemental 150 mg/kg curcumin can improve production performance, antioxidant enzyme activity, and immune function in laying hens under heat stress. To further investigate the regulatory mechanism of curcumin on heat stress-related genes, in total, six samples of three liver tissues from each of 0 mg/kg and 150 mg/kg curcumin test groups were collected for RNA-seq analysis. In the transcriptome analysis, we reported for the first time that the genes related to heat stress of mRNA, such as HSPA8, HSPH1, HSPA2, and DNAJA4, were co-expressed with lncRNA such as XLOC010450, XLOC037987, XLOC053511, XLOC061207, and XLOC100318, and all of these genes are shown to be down-regulated. These findings provide a scientific basis for the possible benefits of dietary curcumin addition in heat-stressed laying hens.
Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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