Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12
Nanomedicine in Bladder Cancer Therapy
Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology
TRPA1 Influences Staphylococcus aureus Skin Infection in Mice and Associates with HIF-1a and MAPK Pathway Modulation
The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair?

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 and Molecular Biology) / CiteScore - Q1 (Inorganic Chemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 18.1 days after submission; acceptance to publication is undertaken in 2.8 days (median values for papers published in this journal in the first half of 2024).
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, Stresses, Lymphatics and SynBio.

Impact Factor: 4.9 (2023); 5-Year Impact Factor: 5.6 (2023)

Imprint Information Journal Flyer Open Access ISSN: 1422-0067

Latest Articles

19 pages, 2375 KiB

Open AccessReview

Unraveling the Bone–Brain Axis: A New Frontier in Parkinson’s Disease Research

by Tingting Liu, Haojie Wu, Jingwen Li, Chaoyang Zhu and Jianshe Wei

Int. J. Mol. Sci. 2024, 25(23), 12842; https://doi.org/10.3390/ijms252312842 (registering DOI) - 29 Nov 2024

Abstract

Parkinson’s disease (PD), as a widespread neurodegenerative disorder, significantly impacts patients’ quality of life. Its primary symptoms include motor disturbances, tremor, muscle stiffness, and balance disorders. In recent years, with the advancement of research, the concept of the bone–brain axis has gradually become a focal point in the field of PD research. The bone–brain axis refers to the interactions and connections between the skeletal system and the central nervous system (CNS), playing a crucial role in the pathogenesis and pathological processes of PD. The purpose of this review is to comprehensively and deeply explore the bone–brain axis in PD, covering various aspects such as the complex relationship between bone metabolism and PD, the key roles of neurotransmitters and hormones in the bone–brain axis, the role of inflammation and immunity, microRNA (miRNA) functional regulation, and potential therapeutic strategies. Through a comprehensive analysis and in-depth discussion of numerous research findings, this review aims to provide a solid theoretical foundation for a deeper understanding of the pathogenesis of PD and to offer strong support for the development of new treatment methods. Full article

(This article belongs to the Section Molecular Biology)

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24 pages, 725 KiB

Open AccessReview

Antibiofilm Effects of Novel Compounds in Otitis Media Treatment: Systematic Review

by Ana Jotic, Katarina Savic Vujovic, Andja Cirkovic, Dragana D. Božić, Snezana Brkic, Nikola Subotic, Bojana Bukurov, Aleksa Korugic and Ivana Cirkovic

Int. J. Mol. Sci. 2024, 25(23), 12841; https://doi.org/10.3390/ijms252312841 (registering DOI) - 29 Nov 2024

Abstract

Otitis media (OM) is a frequent disease with incidence rate of 5300 cases per 100,000 people. Recent studies showed that polymicrobial biofilm formation represents a significant pathogenic mechanism in recurrent and chronic forms of OM. Biofilm enables bacteria to resist antibiotics that would typically be recommended in guidelines, contributing to the ineffectiveness of current antimicrobial strategies. Given the challenges of successfully treating bacterial biofilms, there is an growing interest in identifying novel and effective compounds to overcome antibacterial resistance. The objective of this review was to provide an overview of the novel compounds with antibiofilm effects on bacterial biofilm formed by clinical isolates of OM. The systematic review included studies that evaluated antibiofilm effect of novel natural or synthetic compounds on bacterial biofilm formed from clinical isolates obtained from patients with OM. The eligibility criteria were defined using the PICOS system: (P) Population: all human patients with bacterial OM; (I) Intervention: novel natural or synthetic compound with biofilm effect; (C) Control standard therapeutic antimicrobial agents or untreated biofilms, (O) Outcome: antibiofilm effect (biofilm inhibition, biofilm eradication), (S) Study design. The PRISMA protocol for systematic reviews and meta-analysis was followed. From 3564 potentially eligible studies, 1817 duplicates were removed, and 1705 were excluded according to defined exclusion criteria. A total of 41 studies with available full texts were retrieved by two independent authors. Fifteen articles were selected for inclusion in the systematic review which included 125 patients with OM. A total of 17 different novel compounds were examined, including N-acetyl-L-cysteine (NAC), tea tree oil, xylitol, eugenol, Aloe barbadensis, Zingiber officinale, Curcuma longa, Acacia arabica, antisense peptide nucleic acids, probiotics Streptococcus salivarius and Streptococcus oralis, Sodium 2-mercaptoethanesulfonate (MESNA), bioactive glass, green synthesized copper oxide nanoparticles, radish, silver nanoparticles and acetic acid. Staphylococcus aureus was the most commonly studied pathogen, followed by Pseudomonas aeruginosa and Haemophilus influenzae. Biofilm inhibition only by an examined compound was assessed in six studies; biofilm eradication in four studies, and both biofilm inhibition and biofilm eradication were examined in five studies. This systematic review indicates that some compounds like NAC, prebiotics, nanoparticles and MESNA that have significant effects on biofilm are safe and could be researched more extensively for further clinical use. However, a lack of data about reliable and efficient compounds used in therapy of different types of otitis media still remains in the literature. Full article

(This article belongs to the Special Issue Biofilm Antimicrobial Strategies: Outlook and Future Perspectives)

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20 pages, 1376 KiB

Open AccessReview

Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia

by Ilaria Sergio, Claudia Varricchio, Federica Squillante, Noemi Martina Cantale Aeo, Antonio Francesco Campese and Maria Pia Felli

Int. J. Mol. Sci. 2024, 25(23), 12839; https://doi.org/10.3390/ijms252312839 (registering DOI) - 29 Nov 2024

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed to T-cell lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% of adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis and therapy resistance. Notch inhibition is a promising therapeutic target for personalized medicine, and a variety of strategies to prevent Notch activation, including γ-secretase (GS) inhibitors (GSIs) and antibodies neutralizing Notch receptors or ligands, have been developed. Disruption of apoptosis is pivotal in cancer development and progression. Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use. Full article

(This article belongs to the Special Issue Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders—3rd Edition)

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21 pages, 2030 KiB

Open AccessReview

Anemia and Mineral Bone Disorder in Kidney Disease Patients: The Role of FGF-23 and Other Related Factors

by Nazareno Carullo, David Sorbo, Teresa Faga, Sara Pugliese, Maria Teresa Zicarelli, Davide Costa, Nicola Ielapi, Yuri Battaglia, Antonio Pisani, Giuseppe Coppolino, Davide Bolignano, Ashour Michael, Raffaele Serra and Michele Andreucci

Int. J. Mol. Sci. 2024, 25(23), 12838; https://doi.org/10.3390/ijms252312838 (registering DOI) - 29 Nov 2024

Abstract

Anemia and mineral and bone disorder (MBD) are significant complications of chronic kidney disease (CKD). The erythropoietin (Epo) pathway plays a key role in both of these processes in CKD. Another molecule that plays an important role in CKD-MBD is fibroblast growth factor (FGF)-23, whose main role is to maintain serum phosphate levels in the normal range, acting via its co-receptor Klotho; however, its activity may also be related to anemia and inflammation. In this review, the regulation of Epo and FGF-23 and the molecular mechanisms of their action are outlined. Furthermore, the complex interaction between EPO and FGF-23 is discussed, as well as their association with other anemia-related factors and processes such as Klotho, vitamin D, and iron deficiency. Together, these may be part of a “kidney–bone marrow–bone axis” that promotes CKD-MBD. Full article

(This article belongs to the Special Issue Molecular Advances and Therapeutic Strategies in Renal Failure)

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16 pages, 2747 KiB

Open AccessArticle

A Novel 14mer Peptide Inhibits Autophagic Flux via Selective Activation of the mTORC1 Signalling Pathway: Implications for Alzheimer’s Disease

by Cloe García Porta, Kashif Mahfooz, Joanna Komorowska, Sara Garcia-Rates and Susan Greenfield

Int. J. Mol. Sci. 2024, 25(23), 12837; https://doi.org/10.3390/ijms252312837 (registering DOI) - 29 Nov 2024

Abstract

During development, a 14mer peptide, T14, modulates cell growth via the α-7 nicotinic acetylcholine receptor (α7 nAChR). However, this process could become excitotoxic in the context of the adult brain, leading to pathologies such as Alzheimer’s disease (AD). Recent work shows that T14 acts selectively via the mammalian target of rapamycin complex 1 (mTORC1). This pathway is essential for normal development but is overactive in AD. The triggering of mTORC1 has also been associated with the suppression of autophagy, commonly observed in ageing and neurodegeneration. We therefore investigated the relationship between T14 and autophagic flux in tissue cultures, mouse brain slices, and human Alzheimer’s disease hippocampus. Here, we demonstrate that T14 and p-mTOR s2448 expression significantly increases in AD human hippocampus, which was associated with the gradual decrease in the autophagosome number across Braak stages. During development, the reduction in T14 positively correlated with pTau (Ser202, Thr205) and two selective autophagy receptors: p62 and optineurin. In vitro studies also indicated that T14 increases p-mTOR s2448 expression, resulting in the aggregation of polyubiquinated substances. The effective blockade of T14 via its cyclic variant, NBP14, has been validated in vitro, in vivo, and ex vivo. In this study, NBP14 significantly attenuated p-mTOR s2448 expression and restored normal autophagic flux, as seen with rapamycin. We conclude that T14 acts at the α-7 receptor to selectively activate the mTORC1 pathway and consequently inhibit autophagic flux. Hence, this study describes a further step in the process by which T14 could drive neurodegeneration. Full article

(This article belongs to the Special Issue Advances in Synaptic Transmission and Plasticity)

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17 pages, 2383 KiB

Open AccessReview

Gut Microbiota–microRNA Interactions and Obesity Pathophysiology: A Systematic Review of Integrated Studies

by Hushyar Azari, Megan George and Kembra Albracht-Schulte

Int. J. Mol. Sci. 2024, 25(23), 12836; https://doi.org/10.3390/ijms252312836 (registering DOI) - 29 Nov 2024

Abstract

Obesity is the fifth leading cause of death globally and its comorbidities put a high burden on societies and cause disability. In this review, we aim to summarize the interactions and crosstalk between gut microbiota (GM) and micro-RNA (miRNA) in obesity. We searched for the relevant literature through PubMed, Web of Science, Scopus, and Science Direct. The study design is registered in the international prospective register of systematic reviews (Prospero). According to the inclusion criteria, eight studies were eligible for assessment (two studies including human subjects and six studies including animal subjects). We report that the interactions of miRNA and gut microbiota in the context of obesity are diverse and in some cases tissue specific. However, the interactions mediate obesity-associated pathways including the inflammatory response, oxidative stress, insulin signaling, gut permeability, and lipogenesis. To mention the most meaningful results, the expression of adipose tissue miRNA-378a-3p/5p was associated with Bifidobacterium and Akkermansia abundance, the expression of hepatic miRNA-34a was related to the Firmicutes phylum, and the expression of miRNA-122-5p and miRNA-375 was associated with the Bacteroides genus. miRNA-microbiota-associated pathologic pathways seem to provide an intricate, but promising field for future research directed toward the treatment of obesity and its comorbidities. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction, 3rd Edition)

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18 pages, 2224 KiB

Open AccessCommunication

Distribution of the p66Shc Adaptor Protein Among Mitochondrial and Mitochondria—Associated Membranes Fractions in Normal and Oxidative Stress Conditions

by Magdalena Lebiedzinska-Arciszewska, Barbara Pakula, Massimo Bonora, Sonia Missiroli, Yaiza Potes, Patrycja Jakubek-Olszewska, Ines C. M. Simoes, Paolo Pinton and Mariusz R. Wieckowski

Int. J. Mol. Sci. 2024, 25(23), 12835; https://doi.org/10.3390/ijms252312835 (registering DOI) - 29 Nov 2024

Abstract

p66Shc is an adaptor protein and one of the cellular fate regulators since it modulates mitogenic signaling pathways, mitochondrial function, and reactive oxygen species (ROS) production. p66Shc is localized mostly in the cytosol and endoplasmic reticulum (ER); however, under oxidative stress, p66Shc is post-translationally modified and relocates to mitochondria. p66Shc was found in the intermembrane space, where it interacts with cytochrome c, contributing to the hydrogen peroxide generation by the mitochondrial respiratory chain. Our previous studies suggested that p66Shc is localized also in mitochondria-associated membranes (MAM). MAM fraction consists of mitochondria and mostly ER membranes. Contact sites between ER and mitochondria host proteins involved in multiple processes including calcium homeostasis, apoptosis, and autophagy regulation. Thus, p66Shc in MAM could participate in processes related to cell fate determination. Due to reports on various and conditional p66Shc intracellular localization, in the present paper, we describe the allocation of p66Shc pools in different subcellular compartments in mouse liver tissue and HepG2 cell culture. We provide additional evidence for p66Shc localization in MAM. In the present study, we use precisely purified subcellular fraction isolated by differential centrifugation-based protocol from control mouse liver tissue and HepG2 cells and from cells treated with hydrogen peroxide to promote mitochondrial p66Shc translocation. We performed controlled digestion of crude mitochondrial fraction, in which the degradation patterns of p66Shc and MAM fraction marker proteins were comparable. Moreover, we assessed the distribution of the individual ShcA isoforms (p46Shc, p52Shc, and p66Shc) in the subcellular fractions and their contribution to the total ShcA in control mice livers and HepG2 cells. In conclusion, we showed that a substantial pool of p66Shc protein resides in MAM in control conditions and after oxidative stress induction. Full article

(This article belongs to the Special Issue Mitochondrial Biology and Reactive Oxygen Species)

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Abstract

Obesity is known to affect various tissues and contribute to conditions such as neuroinflammation. However, the specific mechanisms and time-dependent progression of these effects across different tissues remain unclear. In this study, we monitored gene expression at intervals to examine the effects of a high-fat diet (HFD) on brain, liver, adipose, and muscle tissues in male C57/BJ mice, with a particular focus on neuroinflammation. Early inflammatory responses exhibit a progression that starts in the liver, extends to adipose tissue, and subsequently involves muscle and brain tissues. Although the brain did not show significant gene expression of inflammatory responses, mechanisms leading to neuroinflammation increased after 24 weeks, possibly through systemic chronic inflammation (SCI). Notably, mitochondrial complex I activity serves as a biomarker to indicate the inflammatory transition from the liver to adipose and other tissues caused by SCI. These similar gene expression dynamics were also observed in the hippocampus of Alzheimer’s patients and in an Alzheimer’s mouse model treated with a HFD. These results suggest that initially, the brain suppresses inflammatory responses, including interferon-gamma (IFN-γ), more than other tissues in response to a HFD. However, at the onset of SCI, the brain eventually exhibits inflammatory dynamics similar to those of other tissues. This underscores the significance of our findings, indicating that the early kinetics of chronic IFN-γ response and mitochondrial complex I activity inhibition serve as crucial biomarkers, emerging early in various conditions, including obesity and aging. Full article

34 pages, 5759 KiB

Open AccessArticle

Expression and Immune Response Profiles in Nile Tilapia (Oreochromis niloticus) and European Sea Bass (Dicentrarchus labrax) During Pathogen Challenge and Infection

by Ahmed A. Saleh, Asmaa Z. Mohamed, Shaaban S. Elnesr, Asmaa F. Khafaga, Hamada Elwan, Mohamed F. Abdel-Aziz, Asmaa A. Khaled and Elsayed E. Hafez

Int. J. Mol. Sci. 2024, 25(23), 12829; https://doi.org/10.3390/ijms252312829 (registering DOI) - 28 Nov 2024

Abstract

Nile tilapia (Oreochromis niloticus) and European sea bass (Dicentrarchus labrax) are economically significant species in Mediterranean countries, serving essential roles in the aquaculture industry due to high market demand and nutritional value. They experience substantial losses from bacterial pathogens Vibrio anguillarum and Streptococcus iniae, particularly at the onset of the summer season. The immune mechanisms involved in fish infections by V. anguillarum and S. iniae remain poorly understood. This study investigated their impact through experiments with control and V. anguillarum- and S. iniae-infected groups for each species. Blood samples were collected at 1, 3, and 7 days post bacterial injection to assess biochemical and immunological parameters, including enzyme activities (AST and ALT), oxidative markers (SOD, GPX, CAT, and MDA), and leukocyte counts. Further analyses included phagocyte activity, lysozyme activity, IgM levels, and complement C3 and C4 levels. Muscle tissues were sampled at 1, 3, and 7 days post injection to assess mRNA expression levels of 18 immune-relevant genes. The focus was on cytokines and immune-related genes, including pro-inflammatory cytokines (TNF-α, TNF-β, IL-2, IL-6, IL-8, IL-12, and IFN-γ), major histocompatibility complex components (MHC-IIα and MHC-IIβ), cytokine receptors (CXCL-10 and CD4-L2), antimicrobial peptides (Pleurocidin and β-defensin), immune regulatory peptides (Thymosin β12, Leap 2, and Lysozyme g), and Galectins (Galectin-8 and Galectin-9). β-actin was used as the housekeeping gene for normalization. Significant species-specific responses were observed in N. Tilapia and E. Sea Bass when infected with V. anguillarum and S. iniae, highlighting differences in biochemical, immune, and gene expression profiles. Notably, in N. Tilapia, AST levels significantly increased by day 7 during S. iniae infection, reaching 45.00 ± 3.00 (p < 0.05), indicating late-stage acute stress or tissue damage. Conversely, E. Sea Bass exhibited a significant rise in ALT levels by day 7 in the S. iniae group, peaking at 33.5 ± 3.20 (p < 0.05), suggesting liver distress or a systemic inflammatory response. On the immunological front, N. Tilapia showed significant increases in respiratory burst activity on day 1 for both pathogens, with values of 0.28 ± 0.03 for V. anguillarum and 0.25 ± 0.02 for S. iniae (p < 0.05), indicating robust initial immune activation. Finally, the gene expression analysis revealed a pronounced peak of TNF-α in E. Sea Bass by day 7 post V. anguillarum infection with a fold change of 6.120, suggesting a strong species-specific pro-inflammatory response strategy. Understanding these responses provides critical insights for enhancing disease management and productivity in aquaculture operations. Full article

(This article belongs to the Special Issue Fish Immunology, 5th Edition)

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