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
The Role of Structural Variants in the Genetic Architecture of Parkinson’s Disease
Int. J. Mol. Sci. 2024, 25(9), 4801; https://doi.org/10.3390/ijms25094801 (registering DOI) - 27 Apr 2024
Abstract
Parkinson’s disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form
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Parkinson’s disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods. Yet, these forms of genetic variation play crucial roles in gene expression and regulation in the human brain and are causative of numerous neurological disorders, including forms of PD. This review aims to provide a comprehensive overview of our current understanding of the involvement of coding and noncoding SVs in the genetic architecture of PD.
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(This article belongs to the Special Issue Understanding the Role of Non-coding DNA in Neurodegenerative Disease)
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Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation
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Rukiye Tuna, Wenjuan Yi, Esmeralda Crespo Cruz, JP Romero, Yi Ren, Jingjiao Guan, Yan Li, Yuefan Deng, Danny Bluestein, Zixiang Leonardo Liu and Jawaad Sheriff
Int. J. Mol. Sci. 2024, 25(9), 4800; https://doi.org/10.3390/ijms25094800 (registering DOI) - 27 Apr 2024
Abstract
Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s ) relies on platelet activation and coagulation. Thrombosis at elevated
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Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s ) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s ) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.
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(This article belongs to the Special Issue The Role of Platelets in Development and Disease: Thrombosis across the Lifespan)
Open AccessArticle
Hydroxytyrosol, a Promising Supplement in the Management of Human Stroke: An Exploratory Study
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Ángela Naranjo, Mª Josefa Álvarez-Soria, Pilar Aranda-Villalobos, Ana Mª Martínez-Rodríguez, Esther Martínez-Lara and Eva Siles
Int. J. Mol. Sci. 2024, 25(9), 4799; https://doi.org/10.3390/ijms25094799 (registering DOI) - 27 Apr 2024
Abstract
Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined
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Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined this effect in humans. Particularly, a nutritional supplement containing 15 mg of HT/day was administered to patients 24 h after the onset of stroke, for 45 days. Biochemical and oxidative-stress-related parameters, blood pressure levels, serum proteome, and neurological and functional outcomes were evaluated at 45 and 90 days and compared to a control group. The main findings were that the daily administration of HT after stroke could: (i) favor the decrease in the percentage of glycated hemoglobin and diastolic blood pressure, (ii) control the increase in nitric oxide and exert a plausible protective effect in oxidative stress, (iii) modulate the evolution of the serum proteome and, particularly, the expression of apolipoproteins, and (iv) be beneficial for certain neurological and functional outcomes. Although a larger trial is necessary, this study suggests that HT could be a beneficial nutritional complement in the management of human stroke.
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(This article belongs to the Special Issue Health Promoting Benefits of Natural Products and Functional Foods)
Open AccessArticle
Potential Involvement of the South American Lungfish Intelectin-2 in Innate-Associated Immune Modulation
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Gabriela Patrícia Martins de Almeida Bernardes, Gustavo Marques Serra, Lucas da Silva e Silva, Maíra Pompeu Martins, Louise Neiva Perez, Fábio Alberto de Molfetta, Agenor Valadares Santos and Maria Paula Cruz Schneider
Int. J. Mol. Sci. 2024, 25(9), 4798; https://doi.org/10.3390/ijms25094798 (registering DOI) - 27 Apr 2024
Abstract
Intelectins belong to a family of lectins with specific and transitory carbohydrate interaction capabilities. These interactions are related to the activity of agglutinating pathogens, as intelectins play a significant role in immunity. Despite the prominent immune defense function of intelectins, limited information about
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Intelectins belong to a family of lectins with specific and transitory carbohydrate interaction capabilities. These interactions are related to the activity of agglutinating pathogens, as intelectins play a significant role in immunity. Despite the prominent immune defense function of intelectins, limited information about its structural characteristics and carbohydrate interaction properties is available. This study investigated an intelectin transcript identified in RNA-seq data obtained from the South American lungfish (Lepidosiren paradoxa), namely LpITLN2-B. The structural analyses predicted LpITLN2-B to be a homo-trimeric globular protein with the fibrinogen-like functional domain (FReD), exhibiting a molecular mass of 57 kDa. The quaternary structure is subdivided into three monomers, A, B, and C, and each domain comprises 11 β-sheets: an anti-parallel β-sheet, a β-hairpin, and a disordered β-sheet structure. Molecular docking demonstrates a significant interaction with disaccharides rather than monosaccharides. The preferential interaction with disaccharides highlights the potential interaction with pathogen molecules, such as LPS and Poly(I:C). The hemagglutination assay inhibited lectins activity, especially maltose and sucrose, highlighting lectin activity in L. paradoxa samples. Overall, our results show the potential relevance of LpITLN2-B in L. paradoxa immune defense against pathogens.
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(This article belongs to the Special Issue Fish Immunology 4.0)
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In Vitro Evaluation of Phytobiotic Mixture Antibacterial Potential against Enterococcus spp. Strains Isolated from Broiler Chicken
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Karolina Wódz, Karolina A. Chodkowska, Hubert Iwiński, Henryk Różański and Jakub Wojciechowski
Int. J. Mol. Sci. 2024, 25(9), 4797; https://doi.org/10.3390/ijms25094797 (registering DOI) - 27 Apr 2024
Abstract
Enterococcus spp. are normal intestinal tract microflorae found in poultry. However, the last decades have shown that several species, e.g., Enterococcus cecorum, have become emerging pathogens in broilers and may cause numerous losses in flocks. In this study, two combinations (H1 and
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Enterococcus spp. are normal intestinal tract microflorae found in poultry. However, the last decades have shown that several species, e.g., Enterococcus cecorum, have become emerging pathogens in broilers and may cause numerous losses in flocks. In this study, two combinations (H1 and H2) of menthol, 1,8-cineol, linalool, methyl salicylate, γ-terpinene, p-cymene, trans-anethole, terpinen-4-ol and thymol were used in an in vitro model, analyzing its effectiveness against the strains E. cecorum, E. faecalis, E. faecium, E. hirae and E. gallinarum isolated from broiler chickens from industrial farms. To identify the isolated strains classical microbiological methods and VITEK 2 GP cards were used. Moreover for E. cecorum a PCR test was used.. Antibiotic sensitivity (MIC) tests were performed for all the strains. For the composition H1, the effective dilution for E. cecorum and E. hirae strains was 1:512, and for E. faecalis, E. faecium and E. gallinarum, 1:1024. The second mixture (H2) showed very similar results with an effectiveness at 1:512 for E. cecorum and E. hirae and 1:1024 for E. faecalis, E. faecium and E. gallinarum. The presented results suggest that the proposed composition is effective against selected strains of Enterococcus in an in vitro model, and its effect is comparable to classical antibiotics used to treat this pathogen in poultry. This may suggest that this product may also be effective in vivo and provide effective support in the management of enterococcosis in broiler chickens.
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(This article belongs to the Special Issue Recent Research on Antimicrobial Agents)
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Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System
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Sonia Spinelli, Maurizio Bruschi, Mario Passalacqua, Lucrezia Guida, Mirko Magnone, Laura Sturla and Elena Zocchi
Int. J. Mol. Sci. 2024, 25(9), 4796; https://doi.org/10.3390/ijms25094796 (registering DOI) - 27 Apr 2024
Abstract
The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose
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The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.
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(This article belongs to the Special Issue Hormone/Receptor System in Human Diseases)
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EGCG Disrupts the LIN28B/Let-7 Interaction and Reduces Neuroblastoma Aggressiveness
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Simona Cocchi, Valentina Greco, Viktoryia Sidarovich, Jacopo Vigna, Francesca Broso, Diana Corallo, Jacopo Zasso, Angela Re, Emanuele Filiberto Rosatti, Sara Longhi, Andrea Defant, Federico Ladu, Vanna Sanna, Valentina Adami, Vito G. D'Agostino, Mattia Sturlese, Mario Sechi, Sanja Aveic, Ines Mancini, Denise Sighel and Alessandro Quattroneadd
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Int. J. Mol. Sci. 2024, 25(9), 4795; https://doi.org/10.3390/ijms25094795 (registering DOI) - 27 Apr 2024
Abstract
Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology,
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Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.
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(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)
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Light Supplementation in Pitaya Orchards Induces Pitaya Flowering in Winter by Promoting Phytohormone Biosynthesis
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Meng Wang, Jiaxue Li, Tao Li, Shaoling Kang, Senrong Jiang, Jiaquan Huang and Hua Tang
Int. J. Mol. Sci. 2024, 25(9), 4794; https://doi.org/10.3390/ijms25094794 (registering DOI) - 27 Apr 2024
Abstract
The interaction between light and phytohormones is crucial for plant growth and development. The practice of supplementing light at night during winter to promote pitaya flowering and thereby enhance yield has been shown to be crucial and widely used. However, it remains unclear
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The interaction between light and phytohormones is crucial for plant growth and development. The practice of supplementing light at night during winter to promote pitaya flowering and thereby enhance yield has been shown to be crucial and widely used. However, it remains unclear how supplemental winter light regulates phytohormone levels to promote flowering in pitaya. In this study, through analyzing the transcriptome data of pitaya at four different stages (NL, L0, L1, L2), we observed that differentially expressed genes (DEGs) were mainly enriched in the phytohormone biosynthesis pathway. We further analyzed the data and found that cytokinin (CK) content first increased at the L0 stage and then decreased at the L1 and L2 stages after supplemental light treatment compared to the control (NL). Gibberellin (GA), auxin (IAA), salicylic acid (SA), and jasmonic acid (JA) content increased during the formation of flower buds (L1, L2 stages). In addition, the levels of GA, ethylene (ETH), IAA, and abscisic acid (ABA) increased in flower buds after one week of development (L2f). Our results suggest that winter nighttime supplemental light can interact with endogenous hormone signaling in pitaya, particularly CK, to regulate flower bud formation. These results contribute to a better understanding of the mechanism of phytohormone interactions during the induction of flowering in pitaya under supplemental light in winter.
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(This article belongs to the Section Molecular Plant Sciences)
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Fetal Kidney Grafts and Organoids from Microminiature Pigs: Establishing a Protocol for Production and Long-Term Cryopreservation
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Yuka Inage, Koki Fujimori, Masaki Takasu, Kenji Matsui, Yoshitaka Kinoshita, Keita Morimoto, Nagisa Koda, Shutaro Yamamoto, Kentaro Shimada, Takashi Yokoo and Eiji Kobayashi
Int. J. Mol. Sci. 2024, 25(9), 4793; https://doi.org/10.3390/ijms25094793 (registering DOI) - 27 Apr 2024
Abstract
Fetal organs and organoids are important tools for studying organ development. Recently, porcine organs have garnered attention as potential organs for xenotransplantation because of their high degree of similarity to human organs. However, to meet the prompt demand for porcine fetal organs by
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Fetal organs and organoids are important tools for studying organ development. Recently, porcine organs have garnered attention as potential organs for xenotransplantation because of their high degree of similarity to human organs. However, to meet the prompt demand for porcine fetal organs by patients and researchers, effective methods for producing, retrieving, and cryopreserving pig fetuses are indispensable. Therefore, in this study, to collect fetuses for kidney extraction, we employed cesarean sections to preserve the survival and fertility of the mother pig and a method for storing fetal kidneys by long-term cryopreservation. Subsequently, we evaluated the utility of these two methods. We confirmed that the kidneys of pig fetuses retrieved by cesarean section that were cryopreserved for an extended period could resume renal growth when grafted into mice and were capable of forming renal organoids. These results demonstrate the usefulness of long-term cryopreserved fetal pig organs and strongly suggest the effectiveness of our comprehensive system of pig fetus retrieval and fetal organ preservation, thereby highlighting its potential as an accelerator of xenotransplantation research and clinical innovation.
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(This article belongs to the Special Issue Recent Research in Stem Cells to Organoids)
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Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology
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Sevastianos Chatzidavid, Pagona Flevari, Ioanna Tombrou, Georgios Anastasiadis and Maria Dimopoulou On behalf of the International Hemoglobinopathy Research Network (INHERENT)
Int. J. Mol. Sci. 2024, 25(9), 4792; https://doi.org/10.3390/ijms25094792 (registering DOI) - 27 Apr 2024
Abstract
Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6–10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity
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Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6–10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is currently focused on the potential role of genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the transforming growth factor-beta (TGF-β) pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future, as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield reliable results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. This review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.
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(This article belongs to the Special Issue Genetic Modifiers of Hemoglobinopathies: Recent Advances and Future Directions)
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Development, High-Throughput Profiling, and Biopanning of a Large Phage Display Single-Domain Antibody Library
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Hee Eon Lee, Ah Hyun Cho, Jae Hyeon Hwang, Ji Woong Kim, Ha Rim Yang, Taehoon Ryu, Yushin Jung and Sukmook Lee
Int. J. Mol. Sci. 2024, 25(9), 4791; https://doi.org/10.3390/ijms25094791 (registering DOI) - 27 Apr 2024
Abstract
Immunoglobulin G-based monoclonal antibodies (mAbs) have been effective in treating various diseases, but their large molecular size can limit their penetration of tissue and efficacy in multifactorial diseases, necessitating the exploration of alternative forms. In this study, we constructed a phage display library
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Immunoglobulin G-based monoclonal antibodies (mAbs) have been effective in treating various diseases, but their large molecular size can limit their penetration of tissue and efficacy in multifactorial diseases, necessitating the exploration of alternative forms. In this study, we constructed a phage display library comprising single-domain antibodies (sdAbs; or “VHHs”), known for their small size and remarkable stability, using a total of 1.6 × 109 lymphocytes collected from 20 different alpacas, resulting in approximately 7.16 × 1010 colonies. To assess the quality of the constructed library, next-generation sequencing-based high-throughput profiling was performed, analyzing approximately 5.65 × 106 full-length VHH sequences, revealing 92% uniqueness and confirming the library’s diverse composition. Systematic characterization of the library revealed multiple sdAbs with high affinity for three therapeutically relevant antigens. In conclusion, our alpaca sdAb phage display library provides a versatile resource for diagnostics and therapeutics. Furthermore, the library’s vast natural VHH antibody repertoire offers insights for generating humanized synthetic sdAb libraries, further advancing sdAb-based therapeutics.
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(This article belongs to the Special Issue Application of High-Throughput Omics Sequencing in Personalized Medicine)
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Design of Mixed Medicinal Plants, Rich in Polyphenols, Vitamin B2, and Palmitoylethanolamide-Based Supplement to Help Reduce Nerve Pain: A Preclinical Study
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Simone Mulè, Giorgia Rosso, Mattia Botta, Arianna Brovero, Sara Ferrari, Rebecca Galla, Claudio Molinari and Francesca Uberti
Int. J. Mol. Sci. 2024, 25(9), 4790; https://doi.org/10.3390/ijms25094790 (registering DOI) - 27 Apr 2024
Abstract
Neuropathy affects 7–10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between
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Neuropathy affects 7–10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies.
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(This article belongs to the Collection Feature Papers in Bioactives and Nutraceuticals)
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Multi-System-Level Analysis with RNA-Seq on Pterygium Inflammation Discovers Association between Inflammatory Responses, Oxidative Stress, and Oxidative Phosphorylation
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Ye-Ah Kim, Yueun Choi, Tae Gi Kim, Jisu Jeong, Sanghyeon Yu, Taeyoon Kim, Kisung Sheen, Yoonsung Lee, Taesoo Choi, Yong Hwan Park, Min Seok Kang and Man S. Kim
Int. J. Mol. Sci. 2024, 25(9), 4789; https://doi.org/10.3390/ijms25094789 (registering DOI) - 27 Apr 2024
Abstract
A pterygium is a common conjunctival degeneration and inflammatory condition. It grows onto the corneal surface or limbus, causing blurred vision and cosmetic issues. Ultraviolet is a well-known risk factor for the development of a pterygium, although its pathogenesis remains unclear, with only
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A pterygium is a common conjunctival degeneration and inflammatory condition. It grows onto the corneal surface or limbus, causing blurred vision and cosmetic issues. Ultraviolet is a well-known risk factor for the development of a pterygium, although its pathogenesis remains unclear, with only limited understanding of its hereditary basis. In this study, we collected RNA-seq from both pterygial tissues and conjunctival tissues (as controls) from six patients (a total of twelve biological samples) and retrieved publicly available data, including eight pterygium samples and eight controls. We investigated the intrinsic gene regulatory mechanisms closely linked to the inflammatory reactions of pterygiums and compared Asian (Korea) and the European (Germany) pterygiums using multiple analysis approaches from different perspectives. The increased expression of antioxidant genes in response to oxidative stress and DNA damage implies an association between these factors and pterygium development. Also, our comparative analysis revealed both similarities and differences between Asian and European pterygiums. The decrease in gene expressions involved in the three primary inflammatory signaling pathways—JAK/STAT, MAPK, and NF-kappa B signaling—suggests a connection between pathway dysfunction and pterygium development. We also observed relatively higher activity of autophagy and antioxidants in the Asian group, while the European group exhibited more pronounced stress responses against oxidative stress. These differences could potentially be necessitated by energy-associated pathways, specifically oxidative phosphorylation.
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(This article belongs to the Special Issue Application of High-Throughput Omics Sequencing in Personalized Medicine)
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A Structural In Silico Analysis of the Immunogenicity of L-Asparaginase from Penicillium cerradense
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Kellen Cruvinel Rodrigues Andrade, Mauricio Homem-de-Mello, Julia Almeida Motta, Marina Guimarães Borges, Joel Antônio Cordeiro de Abreu, Paula Monteiro de Souza, Adalberto Pessoa, Georgios J. Pappas, Jr. and Pérola de Oliveira Magalhães
Int. J. Mol. Sci. 2024, 25(9), 4788; https://doi.org/10.3390/ijms25094788 (registering DOI) - 27 Apr 2024
Abstract
L-asparaginase is an essential drug used to treat acute lymphoid leukemia (ALL), a cancer of high prevalence in children. Several adverse reactions associated with L-asparaginase have been observed, mainly caused by immunogenicity and allergenicity. Some strategies have been adopted, such as searching for
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L-asparaginase is an essential drug used to treat acute lymphoid leukemia (ALL), a cancer of high prevalence in children. Several adverse reactions associated with L-asparaginase have been observed, mainly caused by immunogenicity and allergenicity. Some strategies have been adopted, such as searching for new microorganisms that produce the enzyme and applying protein engineering. Therefore, this work aimed to elucidate the molecular structure and predict the immunogenic profile of L-asparaginase from Penicillium cerradense, recently revealed as a new fungus of the genus Penicillium and producer of the enzyme, as a motivation to search for alternatives to bacterial L-asparaginase. In the evolutionary relationship, L-asparaginase from P. cerradense closely matches Aspergillus species. Using in silico tools, we characterized the enzyme as a protein fragment of 378 amino acids (39 kDa), including a signal peptide containing 17 amino acids, and the isoelectric point at 5.13. The oligomeric state was predicted to be a homotetramer. Also, this L-asparaginase presented a similar immunogenicity response (T- and B-cell epitopes) compared to Escherichia coli and Dickeya chrysanthemi enzymes. These results suggest a potentially useful L-asparaginase, with insights that can drive strategies to improve enzyme production.
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(This article belongs to the Section Molecular Immunology)
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The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation
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Farai C. Gombedza, Samuel Shin, Jaclyn Sadiua, George B. Stackhouse and Bidhan C. Bandyopadhyay
Int. J. Mol. Sci. 2024, 25(9), 4787; https://doi.org/10.3390/ijms25094787 (registering DOI) - 27 Apr 2024
Abstract
In calcium nephrolithiasis (CaNL), most calcium kidney stones are identified as calcium oxalate (CaOx) with variable amounts of calcium phosphate (CaP), where CaP is found as the core component. The nucleation of CaP could be the first step of CaP+CaOx (mixed) stone formation.
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In calcium nephrolithiasis (CaNL), most calcium kidney stones are identified as calcium oxalate (CaOx) with variable amounts of calcium phosphate (CaP), where CaP is found as the core component. The nucleation of CaP could be the first step of CaP+CaOx (mixed) stone formation. High urinary supersaturation of CaP due to hypercalciuria and an elevated urine pH have been described as the two main factors in the nucleation of CaP crystals. Our previous in vivo findings (in mice) show that transient receptor potential canonical type 3 (TRPC3)-mediated Ca2+ entry triggers a transepithelial Ca2+ flux to regulate proximal tubular (PT) luminal [Ca2+], and TRPC3-knockout (KO; -/-) mice exhibited moderate hypercalciuria and microcrystal formation at the loop of Henle (LOH). Therefore, we utilized TRPC3 KO mice and exposed them to both hypercalciuric [2% calcium gluconate (CaG) treatment] and alkalineuric conditions [0.08% acetazolamide (ACZ) treatment] to generate a CaNL phenotype. Our results revealed a significant CaP and mixed crystal formation in those treated KO mice (KOT) compared to their WT counterparts (WTT). Importantly, prolonged exposure to CaG and ACZ resulted in a further increase in crystal size for both treated groups (WTT and KOT), but the KOT mice crystal sizes were markedly larger. Moreover, kidney tissue sections of the KOT mice displayed a greater CaP and mixed microcrystal formation than the kidney sections of the WTT group, specifically in the outer and inner medullary and calyceal region; thus, a higher degree of calcifications and mixed calcium lithiasis in the kidneys of the KOT group was displayed. In our effort to find the Ca2+ signaling pathophysiology of PT cells, we found that PT cells from both treated groups (WTT and KOT) elicited a larger Ca2+ entry compared to the WT counterparts because of significant inhibition by the store-operated Ca2+ entry (SOCE) inhibitor, Pyr6. In the presence of both SOCE (Pyr6) and ROCE (receptor-operated Ca2+ entry) inhibitors (Pyr10), Ca2+ entry by WTT cells was moderately inhibited, suggesting that the Ca2+ and pH levels exerted sensitivity changes in response to ROCE and SOCE. An assessment of the gene expression profiles in the PT cells of WTT and KOT mice revealed a safeguarding effect of TRPC3 against detrimental processes (calcification, fibrosis, inflammation, and apoptosis) in the presence of higher pH and hypercalciuric conditions in mice. Together, these findings show that compromise in both the ROCE and SOCE mechanisms in the absence of TRPC3 under hypercalciuric plus higher tubular pH conditions results in higher CaP and mixed crystal formation and that TRPC3 is protective against those adverse effects.
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(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease 2.0)
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Open AccessArticle
Berberis vulgaris L. Root Extract as a Multi-Target Chemopreventive Agent against Colon Cancer Causing Apoptosis in Human Colon Adenocarcinoma Cell Lines
by
Anna Och, Marta Kinga Lemieszek, Marek Cieśla, Dariusz Jedrejek, Aleksandra Kozłowska, Sylwia Pawelec and Renata Nowak
Int. J. Mol. Sci. 2024, 25(9), 4786; https://doi.org/10.3390/ijms25094786 (registering DOI) - 27 Apr 2024
Abstract
Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of the chemopreventive action of the plant’s methanolic root
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Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of the chemopreventive action of the plant’s methanolic root extract (BVR) against colon cancer cells. Studies were conducted in human colon adenocarcinoma cell lines (LS180 and HT-29) and control colon epithelial CCD841 CoN cells. According to the MTT assay, after 48 h of cell exposure, the IC50 values were as follows: 4.3, 46.1, and 50.2 µg/mL for the LS180, HT-29, and CCD841 CoN cells, respectively, showing the greater sensitivity of the cancer cells to BVR. The Cell Death Detection ELISAPLUS kit demonstrated that BVR induced programmed cell death only against HT-29 cells. Nuclear double staining revealed the great proapoptotic BVR properties in HT-29 cells and subtle effect in LS180 cells. RT-qPCR with the relative quantification method showed significant changes in the expression of genes related to apoptosis in both the LS180 and HT-29 cells. The genes BCL2L1 (126.86–421.43%), BCL2L2 (240–286.02%), CASP3 (177.19–247.83%), and CASP9 (157.99–243.75%) had a significantly elevated expression, while BCL2 (25–52.03%) had a reduced expression compared to the untreated control. Furthermore, in a panel of antioxidant tests, BVR showed positive effects (63.93 ± 0.01, 122.92 ± 0.01, and 220.29 ± 0.02 mg Trolox equivalents (TE)/g in the DPPH•, ABTS•+, and ORAC assays, respectively). In the lipoxygenase (LOX) inhibition test, BVR revealed 62.60 ± 0.87% of enzyme inhibition. The chemical composition of BVR was determined using a UHPLC-UV-CAD-MS/MS analysis and confirmed the presence of several known alkaloids, including berberine, as well as other alkaloids and two derivatives of hydroxycinnamic acid (ferulic and sinapic acid hexosides). The results are very promising and encourage the use of BVR as a comprehensive chemopreventive agent (anti-inflammatory, antioxidant, and pro-apoptotic) in colorectal cancer, and were widely discussed alongside data from the literature.
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(This article belongs to the Special Issue Antioxidants and Anti-inflammatory, Antiproliferative Activities of Natural Products)
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Open AccessBrief Report
SIRT1 Serum Concentrations in Lipodystrophic Syndromes
by
Luisa Salvatori, Silvia Magno, Giovanni Ceccarini, Rossella Tozzi, Savina Contini, Caterina Pelosini, Ferruccio Santini, Lucio Gnessi and Stefania Mariani
Int. J. Mol. Sci. 2024, 25(9), 4785; https://doi.org/10.3390/ijms25094785 (registering DOI) - 27 Apr 2024
Abstract
Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD+-dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health
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Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD+-dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health by deacetylating target proteins in tissue types including liver, muscle, and adipose. Circulating SIRT1 levels have been found to be reduced in obesity and increased in anorexia nervosa and patients experiencing weight loss. We evaluated circulating SIRT1 levels in relation to fat levels in 32 lipodystrophic patients affected by congenital or acquired LDs compared to non-LD subjects (24 with anorexia nervosa, 22 normal weight, and 24 with obesity). SIRT1 serum levels were higher in LDs than normal weight subjects (mean ± SEM 4.18 ± 0.48 vs. 2.59 ± 0.20 ng/mL) and subjects with obesity (1.7 ± 0.39 ng/mL), whereas they were close to those measured in anorexia nervosa (3.44 ± 0.46 ng/mL). Our findings show that within the LD group, there was no relationship between SIRT1 levels and the amount of body fat. The mechanisms responsible for secretion and regulation of SIRT1 in LD deserve further investigation.
Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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Open AccessReview
The Role of TRP Channels in Sepsis and Colitis
by
Kristina A. Dvornikova, Olga N. Platonova and Elena Y. Bystrova
Int. J. Mol. Sci. 2024, 25(9), 4784; https://doi.org/10.3390/ijms25094784 (registering DOI) - 27 Apr 2024
Abstract
To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel
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To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel activation as well as how these receptors’ activity affects other systems. Moreover, there is a large volume of published studies describing the role of TRP channels in a number of pathological disorders, including inflammatory bowel disease (IBD) and sepsis. Nevertheless, the generalizability of these results is subject to certain limitations. For instance, the study of IBD relies on various animal models and experimental methods, which are unable to precisely imitate the multifactorial chronic disease. The diverse pathophysiological mechanisms and unique susceptibility of animals may account for the inconsistency of the experimental data collected. The main purpose of this study was to conduct a comprehensive review and analysis of existing studies on transient receptor potential (TRP) channels implicating specific models of colitis and sepsis, with particular emphasis on their involvement in pathological disorders such as IBD and sepsis. Furthermore, the text endeavors to evaluate the generalizability of experimental findings, taking into consideration the limitations posed by animal models and experimental methodologies. Finally, we also provide an updated schematic of the most important and possible molecular signaling pathways associated with TRP channels in IBD and sepsis.
Full article
(This article belongs to the Special Issue TRP Channels in Pain and Inflammation 2.0)
Open AccessReview
Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?
by
Flora Guerra, Francesca Romana Ponziani, Ferdinando Cardone, Cecilia Bucci, Emanuele Marzetti and Anna Picca
Int. J. Mol. Sci. 2024, 25(9), 4783; https://doi.org/10.3390/ijms25094783 (registering DOI) - 27 Apr 2024
Abstract
Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles
[...] Read more.
Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.
Full article
(This article belongs to the Special Issue Emerging Role of Immunogenic Cell Death in Cancer Therapy)
Open AccessArticle
Meibum Lipidomic Analysis in Evaporative Dry Eye Subjects
by
Jacobo Garcia-Queiruga, Hugo Pena-Verdeal, Belen Sabucedo-Villamarin, Monica Paz-Tarrio, Esteban Guitian-Fernandez, Carlos Garcia-Resua, Eva Yebra-Pimentel and Maria J. Giraldez
Int. J. Mol. Sci. 2024, 25(9), 4782; https://doi.org/10.3390/ijms25094782 (registering DOI) - 27 Apr 2024
Abstract
Meibomian Glands (MG) are sebaceous glands responsible for the production of meibum, the main component of the Tear Film Lipid Layer (TFLL). The TFLL facilitates the spread of the tear film over the ocular surface, provides stability and reduces tear evaporation. Alterations in
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Meibomian Glands (MG) are sebaceous glands responsible for the production of meibum, the main component of the Tear Film Lipid Layer (TFLL). The TFLL facilitates the spread of the tear film over the ocular surface, provides stability and reduces tear evaporation. Alterations in meibum composition lead to different ocular alterations like Meibomian Gland Dysfunction (MGD) and subsequent Evaporative Dry Eye (EDE). The aim of the present study was to investigate the composition and abundance of meibum lipids and their relationship with eyelid margin abnormalities, lipid layer patterns and MG status. The study utilizes a lipidomic approach to identify and quantify lipids in meibum samples using an Elute UHPLC system. This system considered all four dimensions (mass/charge, retention time, ion mobility and intensity) to provide the accurate identification of lipid species. Samples were categorized as healthy or low/no signs of alteration (group 1) or severe signs of alteration or EDE/MGD (group 2). The current investigation found differences in Variable Importance in Projection lipid abundance between both groups for the MGD signs studied. Changes in meibum composition occur and are related to higher scores in eyelid margin hyperaemia, eyelid margin irregularity, MG orifice plugging, MG loss and lipid layer pattern.
Full article
(This article belongs to the Special Issue Molecular Advances in Dry Eye Syndrome)
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