Journal Description
Cells
Cells
is an international, peer-reviewed, open access journal on cell biology, molecular biology, and biophysics, published semimonthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH) and Society for Regenerative Medicine (Russian Federation) (RPO) are affiliated with Cells and their members receive discounts 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, MEDLINE, PMC, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Cell Biology) / CiteScore - Q1 (General Biochemistry, Genetics and Molecular Biology)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 17.5 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.
- Sections: published in 21 topical sections.
- Companion journal: Organoids.
Impact Factor:
5.1 (2023);
5-Year Impact Factor:
6.0 (2023)
Latest Articles
Stem Cell-Associated Proteins and Extracellular Matrix Composition of the Human Atrioventricular Junction
Cells 2024, 13(24), 2048; https://doi.org/10.3390/cells13242048 (registering DOI) - 11 Dec 2024
Abstract
The human heart regenerates slowly through life, but how new cells are generated is mostly unknown. The atrioventricular junction (AVj) has been indicated as a potential stem cell niche region. Little is known about the protein composition of the human AVj. To map
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The human heart regenerates slowly through life, but how new cells are generated is mostly unknown. The atrioventricular junction (AVj) has been indicated as a potential stem cell niche region. Little is known about the protein composition of the human AVj. To map the extracellular matrix (ECM) and expression of stem cell-related biomarkers, this study compares protein and gene expression patterns in AVj and Left Ventricular (LV) tissues. Biopsies were collected from 15 human hearts. Global quantitative proteomics and mRNA sequencing were used to identify differentially expressed proteins and altered genes. Of the total 4904 identified proteins, 1138 were differently expressed between the AVj and LV. While the top proteins in LV were involved in cardiac motor function and energy regulation, the AVj displayed proteins associated with early cardiomyocyte development, differentiation, proliferation, migration, and hypoxia. Furthermore, several developmental signalling pathways, including TGF-β, TNF, WNT, Notch, and FGF, were represented. RNA-seq data verified that the expressed genes were involved with differentiation, cell growth, proliferation, or ECM organization. Immunohistochemistry confirmed the expression of the stem cell-related biomarkers NPPA and POSTN in the AVj, further strengthening the hypothesis of the AVj as a specialized microenvironment conducive to stem cell niche activity.
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(This article belongs to the Section Cells of the Cardiovascular System)
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Open AccessArticle
A Biorefinery Approach Integrating Lipid and EPS Augmentation Along with Cr (III) Mitigation by Chlorella minutissima
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Sonia Choudhary, Mansi Tiwari and Krishna Mohan Poluri
Cells 2024, 13(24), 2047; https://doi.org/10.3390/cells13242047 (registering DOI) - 11 Dec 2024
Abstract
Abstract: The quest for cleaner and sustainable energy sources is crucial, considering the current scenario of a steep rise in energy consumption and the fuel crisis, exacerbated by diminishing fossil fuel reserves and rising pollutants. In particular, the bioaccumulation of hazardous substances
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Abstract: The quest for cleaner and sustainable energy sources is crucial, considering the current scenario of a steep rise in energy consumption and the fuel crisis, exacerbated by diminishing fossil fuel reserves and rising pollutants. In particular, the bioaccumulation of hazardous substances like trivalent chromium has not only disrupted the fragile equilibrium of the ecological system but also poses significant health hazards to humans. Microalgae emerged as a promising solution for achieving sustainability due to their ability to remediate contaminants and produce greener alternatives such as biofuels. This integrated approach provides an ambitious strategy to address global concerns pertaining to economic stability, environmental degradation, and the energy crisis. This study investigates the intricate defense mechanisms deployed by freshwater microalgae Chlorella minutissima in response to Cr (III) toxicity. The microalga achieved an impressive 92% removal efficiency with an IC50 value of 200 ppm, illustrating its extraordinary resilience towards chromium-induced stress. Furthermore, this research embarked on thorough explorations encompassing morphological, pigment-centric, and biochemical analyses, aimed at revealing the adaptive strategies associated with Cr (III) resilience, as well as the dynamics of carbon pool flow that contribute to enhanced lipid and extracellular polysaccharide (EPS) synthesis. The FAME profile of the biodiesel produced complies with the benchmark established by American and European fuel regulations, emphasizing its suitability as a high-quality vehicular fuel. Elevated levels of ROS, TBARS, and osmolytes (such as glycine-betaine), along with the increased activity of antioxidant enzymes (CAT, GR, and SOD), reveal the activation of robust defense mechanisms against oxidative stress caused by Cr (III). The finding of this investigation presents an effective framework for an algal-based biorefinery approach, integrating pollutant detoxification with the generation of vehicular-quality biodiesel and additional value-added compounds vital for achieving sustainability under the concept of a circular economy.
Full article
(This article belongs to the Special Issue Molecular and Biochemical Mechanisms Elucidating Growth and Cellular Stress Responses of Microalgae)
Open AccessArticle
Elevated IL-6 Expression in Autologous Adipose-Derived Stem Cells Regulates RANKL Mediated Inflammation in Osteoarthritis
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Hyun-Joo Lee, Dae-Yong Kim, Hyeon jeong Noh, Song Yi Lee, Ji Ae Yoo, Samuel Jaeyoon Won, Yoon Sang Jeon, Ji Hoon Baek and Dong Jin Ryu
Cells 2024, 13(24), 2046; https://doi.org/10.3390/cells13242046 - 11 Dec 2024
Abstract
Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise
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Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression.
Full article
(This article belongs to the Special Issue Second Edition of Mesenchymal Stem Cells: Intrinsic/Extrinsic Factors Regulating Stemness, Growth, and Differentiation)
Open AccessReview
iPSC-Derived Biological Pacemaker—From Bench to Bedside
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Quan Duy Duy Vo, Kazufumi Nakamura, Yukihiro Saito, Toshihiro Iida, Masashi Yoshida, Naofumi Amioka, Satoshi Akagi, Toru Miyoshi and Shinsuke Yuasa
Cells 2024, 13(24), 2045; https://doi.org/10.3390/cells13242045 - 11 Dec 2024
Abstract
Induced pluripotent stem cell (iPSC)-derived biological pacemakers have emerged as an alternative to traditional electronic pacemakers for managing cardiac arrhythmias. While effective, electronic pacemakers face challenges such as device failure, lead complications, and surgical risks, particularly in children. iPSC-derived pacemakers offer a promising
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Induced pluripotent stem cell (iPSC)-derived biological pacemakers have emerged as an alternative to traditional electronic pacemakers for managing cardiac arrhythmias. While effective, electronic pacemakers face challenges such as device failure, lead complications, and surgical risks, particularly in children. iPSC-derived pacemakers offer a promising solution by mimicking the sinoatrial node’s natural pacemaking function, providing a more physiological approach to rhythm control. These cells can differentiate into cardiomyocytes capable of autonomous electrical activity, integrating into heart tissue. However, challenges such as achieving cellular maturity, long-term functionality, and immune response remain significant barriers to clinical translation. Future research should focus on refining gene-editing techniques, optimizing differentiation, and developing scalable production processes to enhance the safety and effectiveness of these biological pacemakers. With further advancements, iPSC-derived pacemakers could offer a patient-specific, durable alternative for cardiac rhythm management. This review discusses key advancements in differentiation protocols and preclinical studies, demonstrating their potential in treating dysrhythmias.
Full article
Open AccessReview
Mast Cells and Basophils in Major Viral Diseases: What Are the Correlations with SARS-CoV-2, Influenza A Viruses, HIV, and Dengue?
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Luca Gammeri, Serena Sanfilippo, Clara Alessandrello, Sebastiano Gangemi and Paola Lucia Minciullo
Cells 2024, 13(24), 2044; https://doi.org/10.3390/cells13242044 - 11 Dec 2024
Abstract
The SARS-CoV-2 pandemic has significantly impacted global health and has led the population and the scientific community to live in fear of a future pandemic. Based on viral infectious diseases, innate immunity cells such as mast cells and basophils play a fundamental role
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The SARS-CoV-2 pandemic has significantly impacted global health and has led the population and the scientific community to live in fear of a future pandemic. Based on viral infectious diseases, innate immunity cells such as mast cells and basophils play a fundamental role in the pathogenesis of viral diseases. Understanding these mechanisms could be essential to better study practical therapeutic approaches not only to COVID-19 but also to other viral infections widely spread worldwide, such as influenza A, HIV, and dengue. In this literature review, we want to study these concepts. Mast cells and basophils intervene as a bridge between innate and acquired immunity and seem to have a role in the damage mechanisms during infection and in the stimulation of humoral and cellular immunity. In some cases, these cells can act as reservoirs and favor the replication and spread of the virus in the body. Understanding these mechanisms can be useful not only in therapeutic but also in diagnostic and prognostic perspectives. The prospects of applying artificial intelligence and machine learning algorithms for the creation of very accurate diagnostic/prognostic tools are interesting.
Full article
(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Italy 2024)
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Open AccessArticle
The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice
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Liya G. Kondratyeva, Olga A. Rakitina, Victor V. Pleshkan, Alexey I. Kuzmich, Irina A. Linge, Sofia A. Kondratieva, Eugene V. Snezhkov, Irina V. Alekseenko and Eugene D. Sverdlov
Cells 2024, 13(24), 2043; https://doi.org/10.3390/cells13242043 - 11 Dec 2024
Abstract
It is established that BCG vaccination results in the development of both a specific immune response to mycobacterial infections and a nonspecific (heterologous) immune response, designated as trained immunity (TRIM), to other pathogens. We hypothesized that local BCG immunization may induce an early
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It is established that BCG vaccination results in the development of both a specific immune response to mycobacterial infections and a nonspecific (heterologous) immune response, designated as trained immunity (TRIM), to other pathogens. We hypothesized that local BCG immunization may induce an early immune response in bone marrow and spleen innate immunity cells. The early transcriptomic response of various populations of innate immune cells, including monocytes, neutrophils, and natural killer (NK) cells, to BCG vaccination was examined. To this end, C57Bl/6J mice were subcutaneously immunized with 106 CFU of BCG. Three days following BCG administration, the three cell populations were collected from the control and BCG-vaccinated groups using FACS. All cell populations obtained were utilized for the preparation and sequencing of RNA-seq libraries. The analysis of FACS data revealed an increase in the proportion of splenic NK cells and monocytes 3 days post-vaccination. Transcriptomic analysis revealed the deregulation of genes associated with the regulation of immune response (according to Gene Ontology terms) in NK cells, monocytes, and unsorted bone marrow cells. Two NK cell-specific immune ligands (Tnfsf14 and S100a8) and two bone marrow-specific immune receptors (C5ar1 and Csf2rb) were identified among differentially expressed genes. No alterations were identified in neutrophils in either their percentage or at the transcriptomic level. Thus, in this study, we demonstrated that BCG vaccination provides an early increase in the proportion of murine bone marrow and spleen immune cell populations, as well as transcriptomic alterations in monocytes, NK cells, and non-sorted bone marrow cells. This early innate immune response may be beneficial for enhancing TRIM.
Full article
(This article belongs to the Special Issue Innate Immunity in Health and Disease)
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Open AccessArticle
Common Bed Bugs: Non-Viable Hosts for Trypanosoma rangeli Parasites
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Sanam Meraj, Phillip Phung, Kelvin Lau, Carl Lowenberger and Gerhard Gries
Cells 2024, 13(24), 2042; https://doi.org/10.3390/cells13242042 - 11 Dec 2024
Abstract
The hemoflagellate parasite Trypanosoma rangeli is transmitted by triatomine kissing bugs and may co-infect humans together with its Chagas disease-causing congener T. cruzi. Using real-time quantitative polymerase chain reaction (RT-qPCR) and antimicrobial assays, we studied (i) the temporal and spatial
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The hemoflagellate parasite Trypanosoma rangeli is transmitted by triatomine kissing bugs and may co-infect humans together with its Chagas disease-causing congener T. cruzi. Using real-time quantitative polymerase chain reaction (RT-qPCR) and antimicrobial assays, we studied (i) the temporal and spatial distribution of T. rangeli in common bed bugs, Cimex lectularius, following oral ingestion and hemocoelic injection of T. rangeli, and (ii) the immune responses of bed bugs induced by T. rangeli infections. Irrespective of infection mode, no live T. rangeli were present in the bed bugs’ hemolymph, salivary glands, or feces. On day 1 following infection, the bed bugs strongly upregulated the antimicrobial peptide CL-defensin. Following hemocoelic injection of T. rangeli, live parasites were absent in any bed bug tissues examined throughout the 10-day study period. The ingestion of T. rangeli-infected blood had no significant effect on bed bug survival. Our findings indicate that bed bugs disable the development of T. rangeli within their body, in stark contrast to triatomine kissing bugs, which allow the development and transmission of T. rangeli. Our findings help unravel the intricate relationships between bed bugs and trypanosomes, and they contribute to our understanding of vector biology.
Full article
(This article belongs to the Topic Application of Animal Models: From Physiology to Pathology)
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Open AccessArticle
Sex and Age Differences in Glucocorticoid Signaling After an Aversive Experience in Mice
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Yun Li, Bin Zhang, Youhua Yang, Ping Su, James Nicholas Samsom, Albert H. C. Wong and Fang Liu
Cells 2024, 13(24), 2041; https://doi.org/10.3390/cells13242041 - 10 Dec 2024
Abstract
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Background: glucocorticoids may play an important role in the formation of fear memory, which is relevant to the neurobiology of post-traumatic stress disorder (PTSD). In our previous study, we showed the glucocorticoid receptor (GR) forms a protein complex with FKBP51, which prevents translocation
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Background: glucocorticoids may play an important role in the formation of fear memory, which is relevant to the neurobiology of post-traumatic stress disorder (PTSD). In our previous study, we showed the glucocorticoid receptor (GR) forms a protein complex with FKBP51, which prevents translocation of GR into the nucleus to affect gene expression; this complex is elevated in PTSD patients and by fear-conditioned learning in mice, and disrupting this complex blocks the storage and retrieval of fear-conditioned memories. The timing of release of glucocorticoid relative to the formation of a traumatic memory could be important in this process, and remains poorly understood. Methods and Results: we mapped serum corticosterone over time after fear conditioning in cardiac blood samples from male and female mice, as well as adult and aged mice using ELISA. We show a significant alteration in serum corticosterone after conditioning; notably, levels spike after 30 min but drop lower than unconditioned controls after 24 h. We further investigate the effect of glucocorticoid on GR phosphorylation and localization in HEK 293T cells by Western blot. Hydrocortisone treatment promotes phosphorylation and nuclear translocation of GR. Conclusions: these data contribute to our understanding of the processes linking stress responses to molecular signals and fear memory, which is relevant to understanding the shared mechanisms related to PTSD.
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Open AccessArticle
KSRP Deficiency Attenuates the Course of Pulmonary Aspergillosis and Is Associated with the Elevated Pathogen-Killing Activity of Innate Myeloid Immune Cells
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Vanessa Bolduan, Kim-Alicia Palzer, Frederic Ries, Nora Busch, Andrea Pautz and Matthias Bros
Cells 2024, 13(24), 2040; https://doi.org/10.3390/cells13242040 - 10 Dec 2024
Abstract
The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally, e.g., by reducing the mRNA stability of cytokines. It is known that KSRP binds the AU-rich motifs (ARE) that are often located in the 3′-untranslated part of
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The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally, e.g., by reducing the mRNA stability of cytokines. It is known that KSRP binds the AU-rich motifs (ARE) that are often located in the 3′-untranslated part of mRNA species, encoding dynamically regulated proteins as, for example, cytokines. Innate myeloid immune cells, such as polymorphonuclear neutrophils (PMNs) and macrophages (MACs), eliminate pathogens by multiple mechanisms, including phagocytosis and the secretion of chemo- and cytokines. Here, we investigated the role of KSRP in the phenotype and functions of both innate immune cell types in the mouse model of invasive pulmonary aspergillosis (IPA). Here, KSRP−/− mice showed lower levels of Aspergillus fumigatus conidia (AFC) and an increase in the frequencies of PMNs and MACs in the lungs. Our results showed that PMNs and MACs from KSRP−/− mice exhibited an enhanced phagocytic uptake of AFC, accompanied by increased ROS production in PMNs upon stimulation. A comparison of RNA sequencing data revealed that 64 genes related to inflammatory and immune responses were shared between PMNs and MACs. The majority of genes upregulated in PMNs were involved in metabolic processes, cell cycles, and DNA repair. Similarly, KSRP-deficient PMNs displayed reduced levels of apoptosis. In conclusion, our results indicate that KSRP serves as a critical negative regulator of PMN and MAC anti-pathogen activity.
Full article
(This article belongs to the Special Issue Innate Immunity in Health and Disease)
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Open AccessReview
Alzheimer’s Disease: In Vitro and In Vivo Evidence of Activation of the Plasma Bradykinin-Forming Cascade and Implications for Therapy
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Allen P. Kaplan, Berhane Ghebrehiwet and Kusumam Joseph
Cells 2024, 13(24), 2039; https://doi.org/10.3390/cells13242039 - 10 Dec 2024
Abstract
The plaques associated with Alzheimer’s disease are formed as a result of the aggregation of Aβ peptides, which vary in length from 38 to 43 amino acids. The 1-40 peptide is the most abundant, while the 1-42 peptide appears to be the most
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The plaques associated with Alzheimer’s disease are formed as a result of the aggregation of Aβ peptides, which vary in length from 38 to 43 amino acids. The 1-40 peptide is the most abundant, while the 1-42 peptide appears to be the most destructive to neurons and/or glial cells in a variety of assays. We have demonstrated that aggregated Aβ, a state prior to plaque formation, will activate the plasma bradykinin-forming pathway when tested in vitro. Aggregation is zinc-dependent, optimal at 25–50 µM, and the rate of aggregation is paralleled by the rate of activation of the bradykinin-forming pathway as assessed by plasma kallikrein formation. The aggregation of Aβ 1-38, 1-40, and 1-42 is optimal after incubation for 3 days, 3 h, and under 1 min, respectively. The cascade is initiated by the autoactivation of factor XII upon binding to aggregated Aβ; then, prekallikrein is converted to kallikrein, which cleaves high-molecular-weight kininogen (HK) to release bradykinin. Studies by a variety of other researchers have demonstrated the presence of each “activation-step” in either the plasma or spinal fluid of patients with Alzheimer’s disease, including activated factor XII, kallikrein, and bradykinin itself. There is also evidence that activation is more prominent as dementia worsens. We now have medications that can block each step of the bradykinin-forming pathway as currently employed for the therapy of hereditary angioedema. Given the current state of therapy for Alzheimer’s disease, which includes monoclonal antibodies that retard the rate of progression by 30% at most and have significant side effects, it seems imperative to explore prophylaxis using one of the long-acting agents that target plasma kallikrein or factor XIIa. There is a long-acting bradykinin antagonist in development, and techniques to target kallikrein mRNA to lower levels or knock out the prekallikrein gene are being developed.
Full article
(This article belongs to the Special Issue Behind and beyond Neuroinflammation: State of the Art and New Perspectives)
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Open AccessArticle
SARS-CoV-2 Spike Protein Amplifies the Immunogenicity of Healthy Renal Epithelium in the Presence of Renal Cell Carcinoma
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Maryna Somova, Stefan Simm, Jens Ehrhardt, Janosch Schoon, Martin Burchardt and Pedro Caetano Pinto
Cells 2024, 13(24), 2038; https://doi.org/10.3390/cells13242038 - 10 Dec 2024
Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer, known for its immune evasion and resistance to chemotherapy. Evidence indicates that the SARS-CoV-2 virus may worsen outcomes for RCC patients, as well as patients with diminished renal function. Evidence suggests
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Renal cell carcinoma (RCC) is the most common form of kidney cancer, known for its immune evasion and resistance to chemotherapy. Evidence indicates that the SARS-CoV-2 virus may worsen outcomes for RCC patients, as well as patients with diminished renal function. Evidence suggests that the SARS-CoV-2 virus may exacerbate outcomes in RCC patients and those with impaired renal function. This study explored the unidirectional effects of RCC cells and the SARS-CoV-2 spike protein (S protein) on human renal proximal tubule epithelial cells (RPTECs) using a microphysiological approach. We co-cultured RCC cells (Caki-1) with RPTEC and exposed them to the SARS-CoV-2 S protein under dynamic 3D conditions. The impact on metabolic activity, gene expression, immune secretions, and S protein internalization was evaluated. The SARS-CoV-2 S protein was internalized by RPTEC but poorly interacted with RCC cells. RPTECs exposed to RCC cells and the S protein exhibited upregulated expression of genes involved in immunogenic pathways, particularly those related to antigen processing and presentation via the major histocompatibility complex I (MHCI). Additionally, increased TNF-α secretion suggested a pro-inflammatory response. Metabolic shifts toward glycolysis were observed in RCC co-culture, while the presence of the S protein led to minor changes. The presence of RCC cells amplified the immune-modulatory effects of the SARS-CoV-2 S protein on the renal epithelium, potentially exacerbating renal inflammation and fostering tumor-supportive conditions. These findings suggest that COVID-19 infections can impact renal function in the presence of kidney cancer.
Full article
(This article belongs to the Special Issue Kidney Disease Models, Cellular Mechanism and Potential Treatment)
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Open AccessFeature PaperReview
Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation
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Beatrice Uguagliati and Mariagrazia Grilli
Cells 2024, 13(24), 2037; https://doi.org/10.3390/cells13242037 - 10 Dec 2024
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Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is
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Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and supporting the maintenance and integration of functional neural circuits. The enhanced number of astrocytes in the brain of DS individuals leads to detrimental consequences for brain development. This review summarizes the mechanisms underlying astrocytic dysfunction in DS, and particularly the dysregulation of key signaling pathways, which promote astrogliogenesis at the expense of neurogenesis. It further examines the implications of astrocytic alterations on dendritic branching, spinogenesis and synaptogenesis, and the impact of the abnormal astrocytic number in neural excitability and in the maintenance of the inhibitory/excitatory balance. Identifying deregulated pathways and the consequences of astrocytic alterations in early DS brain development may help in identifying new therapeutic targets, with the ultimate aim of ameliorating the cognitive disability that affects individuals with DS.
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Open AccessReview
The Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder
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Matteo Bonetti, Elisa Borsani and Francesca Bonomini
Cells 2024, 13(24), 2036; https://doi.org/10.3390/cells13242036 - 10 Dec 2024
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Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of
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Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of secondary complications, among which include anxiety, ADHD (attention deficit hyperactivity disorder), cognitive impairment, sleep disorders, sensory alterations, and gastrointestinal issues. So far, no treatment for the core symptoms of ASD has yielded satisfactory results in a clinical setting. Consequently, medical and psychological support for ASD patients has focused on improving quality of life and treating secondary complications. Despite no single cause being identified for the onset and development of ASD, many genetic mutations and risk factors, such as maternal age, fetal exposure to certain drugs, or infections have been linked to the disorder. In preclinical contexts, these correlations have acted as a valuable basis for the development of various murine models that have successfully mimicked ASD-like symptoms and complications. This review aims to summarize the findings of the extensive literature regarding the pharmacological and nutraceutical interventions that have been tested in the main animal models for ASD, and their effects on core symptoms and the anatomical, physiological, or molecular markers of the disorder.
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Open AccessArticle
TCF12 and LncRNA MALAT1 Cooperatively Harness High Cyclin D1 but Low β-Catenin Gene Expression to Exacerbate Colorectal Cancer Prognosis Independently of Metastasis
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Chia-Ming Wu, Chung-Hsing Chen, Kuo-Wang Tsai, Mei-Chen Tan, Fang-Yu Tsai, Shih-Sheng Jiang, Shang-Hung Chen, Wei-Shone Chen, Horng-Dar Wang and Tze-Sing Huang
Cells 2024, 13(24), 2035; https://doi.org/10.3390/cells13242035 - 10 Dec 2024
Abstract
Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor outcomes are less understood. TCF12 is a transcription factor that can be physically associated with the long non-coding RNA MALAT1, creating an alliance with correlated
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Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor outcomes are less understood. TCF12 is a transcription factor that can be physically associated with the long non-coding RNA MALAT1, creating an alliance with correlated expression levels in CRC patients. This TCF12–MALAT1 alliance is linked to poorer prognosis independently of age and metastasis. To identify the downstream effects responsible for this outcome, we analyzed 2312 common target genes of TCF12 and MALAT1, finding involvement in pathways like Aurora B, ATM, PLK1, and non-canonical WNT. We investigated the impact of WNT downstream genes CTNNB1 and CCND1, encoding β-catenin and cyclin D1, respectively, on survival in CRC patients with this alliance. Tumors with higher TCF12 and MALAT1 gene expressions alongside increased β-catenin gene expressions were classified as having a “Pan-CMS-2 pattern”, showing relatively better prognoses. Conversely, tumors with high TCF12, MALAT1, and cyclin D1 gene expressions but low β-catenin expression were categorized as “TMBC pattern”, associated with poor survival, with survival rates dropping sharply from 60% at one year to 30% at three years. This suggests that targeting cyclin D1-associated CDK4/6 could potentially reduce early mortality risks in TMBC patients, supporting personalized medicine approaches.
Full article
(This article belongs to the Special Issue Harnessing the Tumor Microenvironment and Signaling Pathways for Precision Cancer Therapy)
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Open AccessArticle
CycloZ Suppresses TLR4-Driven Inflammation to Reduce Asthma-Like Responses in HDM-Exposed Mouse Models
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Dohyun Lee, Jongsu Jeon, Seoyeong Baek, Onyu Park, Ah-Ram Kim, Myoung-Sool Do and Hoe-Yune Jung
Cells 2024, 13(23), 2034; https://doi.org/10.3390/cells13232034 - 9 Dec 2024
Abstract
Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, and narrowing, with a risk of life-threatening attacks. Most current treatments primarily consist of inhalable steroids, which are not without adverse effects. Recently, there has been growing interest in alternative approaches to
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Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, and narrowing, with a risk of life-threatening attacks. Most current treatments primarily consist of inhalable steroids, which are not without adverse effects. Recently, there has been growing interest in alternative approaches to asthma management. In this study, we investigated the anti-asthmatic effects of the non-steroidal compound CycloZ using acute and chronic mouse models of asthma. Allergic reactions were induced with house dust mite (HDM) extract, and CycloZ or fluticasone propionate (FP) was administered orally or intranasally, respectively. CycloZ significantly ameliorated the HDM-induced robust expression of Th2 cytokines in both models. CycloZ also decreased immune cell infiltration into the lungs and reduced IL-4 and IL-13 cytokine levels in bronchoalveolar lavage fluid (BALF). Moreover, CycloZ greatly attenuated the activation of the TLR-4 pathway, which is involved in HDM recognition and signaling. The beneficial effects of CycloZ were comparable to or even superior to the current steroid treatment, FP, suggesting that CycloZ could be a promising new option for asthma therapy.
Full article
(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms and Therapy of Asthma)
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Open AccessReview
Circular RNAs in Viral Infection and Antiviral Treatment
by
Xiaocai Yin, Hongjun Li and Yan Zhou
Cells 2024, 13(23), 2033; https://doi.org/10.3390/cells13232033 - 9 Dec 2024
Abstract
Circular RNAs (circRNAs) are a class of noncoding RNAs that lack the 5′-cap structure and the 3′ poly(A) tail. Their distinguishing feature is that the 3′ and 5′ ends are covalently linked to form a closed circular structure. CircRNAs have a longer half-life
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Circular RNAs (circRNAs) are a class of noncoding RNAs that lack the 5′-cap structure and the 3′ poly(A) tail. Their distinguishing feature is that the 3′ and 5′ ends are covalently linked to form a closed circular structure. CircRNAs have a longer half-life and stronger ribonuclease resistance compared with linear RNA. Viral infections lead to the production of circRNA molecules through the transcription and splicing mechanisms of host cells. circRNAs are produced from the transcription and splicing of the viral genome or from the splicing reactions of the host cell gene. They participate in regulating the replication of many viruses, including coronaviruses, human herpesviruses, human immunodeficiency virus, and cytomegalovirus. CircRNAs regulate the infection process by modulating circRNA expression in host cells and affect cellular biological processes. Some circRNAs have been proposed as diagnostic markers for viral infections. In this review, we discussed the properties of virus-derived circRNAs, the biological functions of diverse viruses-derived and host circRNAs during viral infections, and the critical role of circRNAs in the host’s antiviral immune defense. Extensive research on the applications of circRNAs can help us better understand gene regulatory networks and disease mechanisms.
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(This article belongs to the Special Issue Non-coding RNAs: Multiple Players in Human Diseases)
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Open AccessArticle
The p.R66W Variant in RAC3 Causes Severe Fetopathy Through Variant-Specific Mechanisms
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Ryota Sugawara, Hidenori Ito, Hidenori Tabata, Hiroshi Ueda, Marcello Scala and Koh-ichi Nagata
Cells 2024, 13(23), 2032; https://doi.org/10.3390/cells13232032 - 9 Dec 2024
Abstract
RAC3 encodes a small GTPase of the Rho family that plays a critical role in actin cytoskeleton remodeling and intracellular signaling regulation. Pathogenic variants in RAC3, all of which reported thus far affect conserved residues within its functional domains, have been linked
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RAC3 encodes a small GTPase of the Rho family that plays a critical role in actin cytoskeleton remodeling and intracellular signaling regulation. Pathogenic variants in RAC3, all of which reported thus far affect conserved residues within its functional domains, have been linked to neurodevelopmental disorders characterized by diverse phenotypic features, including structural brain anomalies and facial dysmorphism (NEDBAF). Recently, a novel de novo RAC3 variant (NM_005052.3): c.196C>T, p.R66W was identified in a prenatal case with fetal akinesia deformation sequence (a spectrum of conditions that interfere with the fetus’s ability to move), and complex brain malformations featuring corpus callosum agenesis, diencephalosynapsis, kinked brainstem, and vermian hypoplasia. To investigate the mechanisms underlying the association between RAC3 deficiency and this unique, distinct clinical phenotype, we explored the pathophysiological significance of the p.R66W variant in brain development. Biochemical assays revealed a modest enhancement in intrinsic GDP/GTP exchange activity and an inhibitory effect on GTP hydrolysis. Transient expression studies in COS7 cells demonstrated that RAC3-R66W interacts with the downstream effectors PAK1, MLK2, and N-WASP but fails to activate SRF-, AP1-, and NFkB-mediated transcription. Additionally, overexpression of RAC3-R66W significantly impaired differentiation in primary cultured hippocampal neurons. Acute expression of RAC3-R66W in vivo by in utero electroporation resulted in impairments in cortical neuron migration and axonal elongation during corticogenesis. Collectively, these findings suggest that the p.R66W variant may function as an activated version in specific signaling pathways, leading to a distinctive and severe prenatal phenotype through variant-specific mechanisms.
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(This article belongs to the Section Cells of the Nervous System)
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Open AccessReview
Extracellular Vesicles and Their Applications in Tumor Diagnostics and Immunotherapy
by
Scott Strum, Valentina Evdokimova, Laszlo Radvanyi and Anna Spreafico
Cells 2024, 13(23), 2031; https://doi.org/10.3390/cells13232031 - 9 Dec 2024
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Extracellular vesicles (EVs) are cell-derived nanoparticles that have attracted significant attention in the investigation of human health and disease, including cancer biology and its clinical management. Concerning cancer, EVs have been shown to influence numerous aspects of oncogenesis, including tumor proliferation and metastasis.
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Extracellular vesicles (EVs) are cell-derived nanoparticles that have attracted significant attention in the investigation of human health and disease, including cancer biology and its clinical management. Concerning cancer, EVs have been shown to influence numerous aspects of oncogenesis, including tumor proliferation and metastasis. EVs can augment the immune system and have been implicated in virtually all aspects of innate and adaptive immunity. With immunotherapy changing the landscape of cancer treatment across multiple disease sites, it is paramount to understand their mechanisms of action and to further improve upon their efficacy. Despite a rapidly growing body of evidence supporting of the utility of EVs in cancer diagnostics and therapeutics, their application in clinical trials involving solid tumors and immunotherapy remains limited. To date, relatively few trials are known to incorporate EVs in this context, mainly employing them as biomarkers. To help address this gap, this review summarizes known applications of EVs in clinical trials and provides a brief overview of the roles that EVs play in cancer biology, immunology, and their proposed implications in immunotherapy. The impetus to leverage EVs in future clinical trials and correlative studies is crucial, as they are ideally positioned to synergize with advancements in multi-omics research to further therapeutic discovery and our understanding of cancer biology.
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Open AccessArticle
Gene-Silencing Therapeutic Approaches Targeting PI3K/Akt/mTOR Signaling in Degenerative Intervertebral Disk Cells: An In Vitro Comparative Study Between RNA Interference and CRISPR–Cas9
by
Masao Ryu, Takashi Yurube, Yoshiki Takeoka, Yutaro Kanda, Takeru Tsujimoto, Kunihiko Miyazaki, Hiroki Ohnishi, Tomoya Matsuo, Naotoshi Kumagai, Kohei Kuroshima, Yoshiaki Hiranaka, Ryosuke Kuroda and Kenichiro Kakutani
Cells 2024, 13(23), 2030; https://doi.org/10.3390/cells13232030 - 9 Dec 2024
Abstract
The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR
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The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway is important in the intervertebral disk, which is the largest avascular, hypoxic, low-nutrient organ in the body. To examine gene-silencing therapeutic approaches targeting PI3K/Akt/mTOR signaling in degenerative disk cells, an in vitro comparative study was designed between small interfering RNA (siRNA)-mediated RNA interference (RNAi) and clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) gene editing. Surgically obtained human disk nucleus pulposus cells were transfected with a siRNA or CRISPR–Cas9 plasmid targeting mTOR, RAPTOR, or RICTOR. Both of the approaches specifically suppressed target protein expression; however, the 24-h transfection efficiency differed by 53.8–60.3% for RNAi and 88.1–89.3% for CRISPR–Cas9 (p < 0.0001). Targeting mTOR, RAPTOR, and RICTOR all induced autophagy and inhibited apoptosis, senescence, pyroptosis, and matrix catabolism, with the most prominent effects observed with RAPTOR CRISPR–Cas9. In the time-course analysis, the 168-h suppression ratio of RAPTOR protein expression was 83.2% by CRISPR–Cas9 but only 8.8% by RNAi. While RNAi facilitates transient gene knockdown, CRISPR–Cas9 provides extensive gene knockout. Our findings suggest that RAPTOR/mTORC1 is a potential therapeutic target for degenerative disk disease.
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(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition)
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Clinical Potential of Novel Microbial Therapeutic LP51 Based on Xerosis-Microbiome Index
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Sukyung Kim, Md Abdur Rahim, Hanieh Tajdozian, Indrajeet Barman, Hyun-A Park, Youjin Yoon, Sujin Jo, Soyeon Lee, Md Sarower Hossen Shuvo, Sung Hae Bae, Hyunji Lee, Sehee Ju, Chae-eun Park, Ho-Kyoung Kim, Jeung Hi Han, Ji-Woong Kim, Sung geon Yoon, Jae Hong Kim, Yang Gyu Choi, Saebim Lee, Hoonhee Seo and Ho-Yeon Songadd
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Cells 2024, 13(23), 2029; https://doi.org/10.3390/cells13232029 - 9 Dec 2024
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Xerosis, characterized by dry, rough skin, causes discomfort and aesthetic concerns, necessitating effective treatment. Traditional treatments often show limited efficacy, prompting the need for innovative therapies. This study highlights the efficacy of microbiome therapeutic LP51, derived from a healthy vaginal microbiome, in improving
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Xerosis, characterized by dry, rough skin, causes discomfort and aesthetic concerns, necessitating effective treatment. Traditional treatments often show limited efficacy, prompting the need for innovative therapies. This study highlights the efficacy of microbiome therapeutic LP51, derived from a healthy vaginal microbiome, in improving xerosis. A double-blind clinical trial involving 43 subjects with dry inner arm skin compared the effects of a 2.9% LP51 extract formulation to a placebo over 4 weeks. The LP51 group exhibited a significant increase in stratum corneum hydration (10.0 A.U.) compared to the placebo group (4.8 A.U.) and a 21.4% decrease in transepidermal water loss (TEWL), whereas the placebo group showed no significant change. LP51 also demonstrated benefits in enhancing skin hydration, improving the skin barrier, and exhibited anti-atopic, anti-inflammatory, and antioxidant properties. Safety was confirmed through in vitro cytotoxicity tests. These effects are attributed to the microbiome-safe component in LP51 and its role in improving xerosis, reflected by an increase in the xerosis-microbiome index, defined by the Firmicutes/Actinobacteria ratio. These findings position microbiome therapeutic LP51 as a promising novel treatment for xerosis.
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