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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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23 pages, 398 KB  
Review
The Genetic Basis of Non-Contact Soft Tissue Injuries-Are There Practical Applications of Genetic Knowledge?
by Beata Borzemska, Paweł Cięszczyk and Cezary Żekanowski
Cells 2024, 13(22), 1828; https://doi.org/10.3390/cells13221828 - 5 Nov 2024
Cited by 2 | Viewed by 3051
Abstract
Physical activity increases the risk of non-contact injuries, mainly affecting muscles, tendons, and ligaments. Genetic factors are recognized as contributing to susceptibility to different types of soft tissue injuries, making this broad condition a complicated multifactorial entity. Understanding genetic predisposition seems to offer [...] Read more.
Physical activity increases the risk of non-contact injuries, mainly affecting muscles, tendons, and ligaments. Genetic factors are recognized as contributing to susceptibility to different types of soft tissue injuries, making this broad condition a complicated multifactorial entity. Understanding genetic predisposition seems to offer the potential for personalized injury prevention and improved recovery strategies. The candidate gene analysis approach used so far, has often yielded inconclusive results. This manuscript reviews the most commonly studied genetic variants in genes involved in the musculoskeletal system’s structure and recovery processes (ACTN3, ACE, CKM, MLCK, AMPD1, IGF2, IL6, TNFα, CCL2, COL1A1, COL5A1, MMP3, and TNC). Referring to the literature, it was highlighted that single-gene analyses provide limited insight. On the other hand, novel genetic testing methods identify numerous variants of uncertain physiological relevance. Distinguishing between functionally important variants, modifying variants, and the thousands of irrelevant variants requires advanced bioinformatics methods and basic multiomics research to identify the key biological pathways contributing to injury susceptibility. Tools like the Total Genotype Score (TGS) and Polygenic Risk Score (PRS) offer a more holistic view by assessing the combined effect of multiple variants. However, these methods, while useful in research, lack clinical applicability. In conclusion, it is too early to determine the clinical implications of genetic variability as a tool for improving well-established training and injury prevention methods, as the predictive power of genetic testing for injury predisposition is currently low. Full article
(This article belongs to the Special Issue Molecular Mechanisms Involved in Musculoskeletal and Other Tissue Injuries and Disruptions—Regenerative Potential of Exercise)
22 pages, 4829 KB  
Article
Host Genetics Background Affects Intestinal Cancer Development Associated with High-Fat Diet-Induced Obesity and Type 2 Diabetes
by Aya Ghnaim, Kareem Midlej, Osayd Zohud, Sama Karram, Arne Schaefer, Yael Houri-Haddad, Iqbal M. Lone and Fuad A. Iraqi
Cells 2024, 13(21), 1805; https://doi.org/10.3390/cells13211805 - 31 Oct 2024
Cited by 2 | Viewed by 1320
Abstract
Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, [...] Read more.
Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, and inflammation due to HFD-induced obesity. Methods: A cohort of 357 Collaborative Cross (CC) mice from 15 lines was fed either a control chow diet (CHD) or HFD for 12 weeks. Body weight was tracked biweekly, and blood glucose was assessed at weeks 6 and 12 via intraperitoneal glucose tolerance tests (IPGTT). At the study’s endpoint, intestinal polyps were counted, and cytokine profiles were analyzed to evaluate the inflammatory response. Results: HFD significantly increased blood glucose levels and body weight, with males showing higher susceptibility to T2D and obesity. Genetic variation across CC lines influenced glucose metabolism, body weight, and polyp development. Mice on HFD developed more intestinal polyps, with males showing higher counts than females. Cytokine analysis revealed diet-induced variations in pro-inflammatory markers like IL-6, IL-17A, and TNF-α, differing by genetic background and sex. Conclusions: Host genetics plays a crucial role in susceptibility to HFD-induced obesity, T2D, CRC, and inflammation. Genetic differences across CC lines contributed to variability in disease outcomes, providing insight into the genetic underpinnings of multimorbidity. This study supports gene-mapping efforts to develop personalized prevention and treatment strategies for these diseases. Full article
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24 pages, 2902 KB  
Review
Advancing CRISPR-Based Solutions for COVID-19 Diagnosis and Therapeutics
by Roaa Hadi, Abhishek Poddar, Shivakumar Sonnaila, Venkata Suryanarayana Murthy Bhavaraju and Shilpi Agrawal
Cells 2024, 13(21), 1794; https://doi.org/10.3390/cells13211794 - 30 Oct 2024
Cited by 1 | Viewed by 4402
Abstract
Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, [...] Read more.
Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, necessitating early and accurate diagnosis for effective management. Although RT-qPCR is a precise molecular technique, it is not immune to false-negative results. In contrast, CRISPR-based detection methods for SARS-CoV-2 offer several advantages: they are cost-effective, time-efficient, highly sensitive, and specific, and they do not require sophisticated instruments. These methods also show promise for scalability, enabling diagnostic tests. CRISPR technology can be customized to target any genomic region of interest, making it a versatile tool with applications beyond diagnostics, including therapeutic development. The CRISPR/Cas systems provide precise gene targeting with immense potential for creating next-generation diagnostics and therapeutics. One of the key advantages of CRISPR/Cas-based therapeutics is the ability to perform multiplexing, where different sgRNAs or crRNAs can target multiple sites within the same gene, reducing the likelihood of viral escape mutants. Among the various CRISPR systems, CRISPR/Cas13 and CARVER (Cas13-assisted restriction of viral expression and readout) are particularly promising. These systems can target a broad range of single-stranded RNA viruses, making them suitable for the diagnosis and treatment of various viral diseases, including SARS-CoV-2. However, the efficacy and safety of CRISPR-based therapeutics must be thoroughly evaluated in pre-clinical and clinical settings. While CRISPR biotechnologies have not yet been fully harnessed to control the current COVID-19 pandemic, there is an optimism that the limitations of the CRISPR/Cas system can be overcome soon. This review discusses how CRISPR-based strategies can revolutionize disease diagnosis and therapeutic development, better preparing us for future viral threats. Full article
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19 pages, 759 KB  
Review
Hepatocellular-Carcinoma-Derived Organoids: Innovation in Cancer Research
by Carlo Airola, Maria Pallozzi, Eleonora Cesari, Lucia Cerrito, Leonardo Stella, Claudio Sette, Felice Giuliante, Antonio Gasbarrini and Francesca Romana Ponziani
Cells 2024, 13(20), 1726; https://doi.org/10.3390/cells13201726 - 18 Oct 2024
Cited by 6 | Viewed by 3705
Abstract
Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using [...] Read more.
Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host’s immunity, the analysis of drug sensitivity tests, and the current limits in this field. Full article
(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives (2nd Edition))
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28 pages, 7251 KB  
Article
The Power of Reagent Titration in Flow Cytometry
by Diana L. Bonilla, Alberta Paul, Jesus Gil-Pulido, Lily M. Park and Maria C. Jaimes
Cells 2024, 13(20), 1677; https://doi.org/10.3390/cells13201677 - 11 Oct 2024
Cited by 5 | Viewed by 9477
Abstract
Flow cytometry facilitates the detection of multiple cell parameters simultaneously with a high level of resolution and throughput, enabling in-depth immunological evaluations. High data resolution in flow cytometry depends on multiple factors, including the concentration of reagents used in the staining protocol, and [...] Read more.
Flow cytometry facilitates the detection of multiple cell parameters simultaneously with a high level of resolution and throughput, enabling in-depth immunological evaluations. High data resolution in flow cytometry depends on multiple factors, including the concentration of reagents used in the staining protocol, and reagent validation and titration should be the first step in any assay optimization. Titration is the process of finding the concentration of the reagent that best resolves a positive signal from the background, with the saturation of all binding sites, and minimal antibody excess. The titration process involves the evaluation of serial reagent dilutions in cells expressing the antigen target for the tested antibody. The concentration of antibody that provides the highest signal to noise ratio is calculated by plotting the percentage of positive cells and the intensity of the fluorescence of the stained cells with respect to the negative events, in a concentration–response curve. The determination of the optimal antibody concentration is necessary to ensure reliable and reproducible results and is required for each sample type, reagent clone and lot, as well as the methods used for cell collection, staining, and storage conditions. If the antibody dilution is too low, the signal will be too weak to be accurately determined, leading to suboptimal data resolution, high variability across measurements, and the underestimation of the frequency of cells expressing a specific marker. The use of excess antibodies could lead to non-specific binding, reagent misuse, and detector overloading with the signal off scale and higher spillover spreading. In this publication, we summarized the titration fundamentals and best practices, and evaluated the impact of using a different instrument, sample, staining, acquisition, and analysis conditions in the selection of the optimal titer and population resolution. Full article
(This article belongs to the Special Issue The Applications of Flow Cytometry: Advances, Challenges, and Trends)
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17 pages, 2965 KB  
Article
Systematic Comparison of CRISPR and shRNA Screens to Identify Essential Genes Using a Graph-Based Unsupervised Learning Model
by Yulian Ding, Connor Denomy, Andrew Freywald, Yi Pan, Franco J. Vizeacoumar, Frederick S. Vizeacoumar and Fang-Xiang Wu
Cells 2024, 13(19), 1653; https://doi.org/10.3390/cells13191653 - 4 Oct 2024
Cited by 1 | Viewed by 2175
Abstract
Generally, essential genes identified using shRNA and CRISPR are not always the same, raising questions about the choice between these two screening platforms. To address this, we systematically compared the performance of CRISPR and shRNA to identify essential genes across different gene expression [...] Read more.
Generally, essential genes identified using shRNA and CRISPR are not always the same, raising questions about the choice between these two screening platforms. To address this, we systematically compared the performance of CRISPR and shRNA to identify essential genes across different gene expression levels in 254 cell lines. As both platforms have a notable false positive rate, to correct this confounding factor, we first developed a graph-based unsupervised machine learning model to predict common essential genes. Furthermore, to maintain the unique characteristics of individual cell lines, we intersect essential genes derived from the biological experiment with the predicted common essential genes. Finally, we employed statistical methods to compare the ability of these two screening platforms to identify essential genes that exhibit differential expression across various cell lines. Our analysis yielded several noteworthy findings: (1) shRNA outperforms CRISPR in the identification of lowly expressed essential genes; (2) both screening methodologies demonstrate strong performance in identifying highly expressed essential genes but with limited overlap, so we suggest using a combination of these two platforms for highly expressed essential genes; (3) notably, we did not observe a single gene that becomes universally essential across all cancer cell lines. Full article
(This article belongs to the Collection Exclusive Papers from Editorial Board Members and Invited Scholars in Cells)
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16 pages, 4211 KB  
Article
An Optimized Liquid Chromatography–Mass Spectrometry Method for Ganglioside Analysis in Cell Lines
by Akeem Sanni, Andrew I. Bennett, Yifan Huang, Isabella Gidi, Moyinoluwa Adeniyi, Judith Nwaiwu, Min H. Kang, Michelle E. Keyel, ChongFeng Gao, C. Patrick Reynolds, Brian Haab and Yehia Mechref
Cells 2024, 13(19), 1640; https://doi.org/10.3390/cells13191640 - 2 Oct 2024
Cited by 2 | Viewed by 3639
Abstract
Gangliosides are glycosphingolipids composed of a sialylated glycan head group and a ceramide backbone. These anionic lipids form lipid rafts and play crucial roles in regulating various proteins involved in signal transduction, adhesion, and cell–cell recognition. Neuroblastoma, a pediatric cancer of the sympathetic [...] Read more.
Gangliosides are glycosphingolipids composed of a sialylated glycan head group and a ceramide backbone. These anionic lipids form lipid rafts and play crucial roles in regulating various proteins involved in signal transduction, adhesion, and cell–cell recognition. Neuroblastoma, a pediatric cancer of the sympathetic nervous system, is treated with intensive chemotherapy, radiation, and an antibody targeting the GD2 ganglioside. Gangliosides are critical in neuroblastoma development and serve as therapeutic targets, making it essential to establish a reliable, rapid, and cost-effective method for profiling gangliosides, particularly one capable of isomeric separation of intact species. In this study, liquid chromatography–mass spectrometry (LC-MS) was optimized using standard gangliosides, followed by the optimization of sphingolipid extraction methods from cell lines by comparing Folch and absolute methanol extraction techniques. Percent recovery and the number of identified sphingolipids were used to evaluate the analytical merits of these methods. A standard gangliosides calibration curve demonstrated excellent linearity (R2 = 0.9961–0.9975). The ZIC-HILIC column provided the best separation of ganglioside GD1 isomers with a 25 min runtime. GD1a elutes before GD1b on the ZIC-HILIC column. Absolute methanol yielded better percent recovery (96 ± 7) and identified 121 different sphingolipids, the highest number between the two extraction methods. The optimized method was applied to profile gangliosides in neuroblastoma (COG-N-683), pancreatic cancer (PSN1), breast cancer (MDA-MB-231BR), and brain tumor (CRL-1620) cell lines. The ganglioside profile of the neuroblastoma cell line COG-N-683 showed an inverse relationship between GD1 and GD2. Ceramide, Hex1Cer, GM1, and GM3 were highly abundant in CRL-1620, PSN1, and MDA-MB-231BR, respectively. These results suggest that our method provides a sensitive, reliable, and high-throughput workflow for ganglioside profiling across different cell types. Full article
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11 pages, 1339 KB  
Communication
Screening a Compound Library to Identify Additives That Boost Cytochrome P450 Enzyme Function in Vascularised Liver Spheres
by Baltasar Lucendo-Villarin, Yu Wang, Sunil K. Mallanna, Erin A. Kimbrel and David C. Hay
Cells 2024, 13(18), 1594; https://doi.org/10.3390/cells13181594 - 22 Sep 2024
Cited by 1 | Viewed by 1773
Abstract
To accurately study human organ function and disease ‘in the dish’, it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a [...] Read more.
To accurately study human organ function and disease ‘in the dish’, it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a multifunctional and highly regenerative organ; however, severe liver damage can have dire consequences for human health. A common cause of liver damage is adverse reactions to prescription drugs. Therefore, the development of predictive liver models that capture human drug metabolism patterns is required to optimise the drug development process. In our study, we aimed to identify compounds that could improve the metabolic function of stem cell-derived liver tissue. Therefore, we screened a compound library to identify additives that improved the maturity of in vitro-engineered human tissue, with the rationale that by taking such an approach, we would be able to fine-tune neonatal and adult cytochrome P450 metabolic function in stem cell-derived liver tissue. Full article
(This article belongs to the Collection Interdisciplinary Approaches to Studying Human Liver Biology and Promoting Organ Regeneration: Understanding the Curse of Prometheus)
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24 pages, 31715 KB  
Article
A Flow Cytometry-Based Examination of the Mouse White Blood Cell Differential in the Context of Age and Sex
by Elise Arlt, Andrea Kindermann, Anne-Kristin Fritsche, Alexander Navarrete Santos, Heike Kielstein and Ivonne Bazwinsky-Wutschke
Cells 2024, 13(18), 1583; https://doi.org/10.3390/cells13181583 - 20 Sep 2024
Cited by 5 | Viewed by 7840
Abstract
Analysis of the white blood cell differential as part of a flow cytometry-based approach is a common routine diagnostic tool used in clinics and research. For human blood, the methodological approach, suitable markers, and gating strategies are well-established. However, there is a lack [...] Read more.
Analysis of the white blood cell differential as part of a flow cytometry-based approach is a common routine diagnostic tool used in clinics and research. For human blood, the methodological approach, suitable markers, and gating strategies are well-established. However, there is a lack of information regarding the mouse blood count. In this article, we deliver a fast and easy protocol for reprocessing mouse blood for the purpose of flow cytometric analysis, as well as suitable markers and gating strategies. We also present two possible applications: for the analysis of the whole blood count, with blood from a cardiac puncture, and for the analysis of a certain leukocyte subset at multiple time points in the framework of a mouse experiment, using blood from the facial vein. Additionally, we provide orientation values by applying the method to 3-month-old and 24-month-old male and female C57BL/6J mice. Our analyses demonstrate differences in the leukocyte fractions depending on age and sex. We discuss the influencing factors and limitations that can affect the results and that, therefore, need to be considered when applying this method. The present study fills the gap in the knowledge related to the rare information on flow cytometric analysis of mouse blood and, thus, lays the foundation for further investigations in this area. Full article
(This article belongs to the Special Issue Flow Cytometry in Immunology Research)
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21 pages, 6630 KB  
Review
Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review
by Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshiyuki Yano, Hiromu Suzuki, Akihiro Miyazaki, Kohichi Takada, Hisashi Uhara, Masato Furuhashi and Fumihito Hikage
Cells 2024, 13(18), 1549; https://doi.org/10.3390/cells13181549 - 14 Sep 2024
Cited by 8 | Viewed by 3230
Abstract
Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various [...] Read more.
Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases. Full article
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15 pages, 2800 KB  
Article
Importance of Transcript Variants in Transcriptome Analyses
by Kevin Vo, Yashica Sharma, Anohita Paul, Ryan Mohamadi, Amelia Mohamadi, Patrick E. Fields and M. A. Karim Rumi
Cells 2024, 13(17), 1502; https://doi.org/10.3390/cells13171502 - 8 Sep 2024
Cited by 4 | Viewed by 2467
Abstract
RNA sequencing (RNA-Seq) has become a widely adopted technique for studying gene expression. However, conventional RNA-Seq analyses rely on gene expression (GE) values that aggregate all the transcripts produced under a single gene identifier, overlooking the complexity of transcript variants arising from different [...] Read more.
RNA sequencing (RNA-Seq) has become a widely adopted technique for studying gene expression. However, conventional RNA-Seq analyses rely on gene expression (GE) values that aggregate all the transcripts produced under a single gene identifier, overlooking the complexity of transcript variants arising from different transcription start sites or alternative splicing. Transcript variants may encode proteins with diverse functional domains, or noncoding RNAs. This study explored the implications of neglecting transcript variants in RNA-Seq analyses. Among the 1334 transcription factor (TF) genes expressed in mouse embryonic stem (ES) or trophoblast stem (TS) cells, 652 were differentially expressed in TS cells based on GE values (365 upregulated and 287 downregulated, ≥absolute 2-fold changes, false discovery rate (FDR) p-value ≤ 0.05). The 365 upregulated genes expressed 883 transcript variants. Further transcript expression (TE) based analyses identified only 174 (<20%) of the 883 transcripts to be upregulated. The remaining 709 transcripts were either downregulated or showed no significant changes. Meanwhile, the 287 downregulated genes expressed 856 transcript variants and only 153 (<20%) of the 856 transcripts were downregulated. The other 703 transcripts were either upregulated or showed no significant change. Additionally, the 682 insignificant TF genes (GE values < absolute 2-fold changes and/or FDR p-values > 0.05) between ES and TS cells expressed 2215 transcript variants. These included 477 (>21%) differentially expressed transcripts (276 upregulated and 201 downregulated, ≥absolute 2-fold changes, FDR p-value ≤ 0.05). Hence, GE based RNA-Seq analyses do not represent accurate expression levels due to divergent transcripts expression from the same gene. Our findings show that by including transcript variants in RNA-Seq analyses, we can generate a precise understanding of a gene’s functional and regulatory landscape; ignoring the variants may result in an erroneous interpretation. Full article
(This article belongs to the Section Cell and Gene Therapy)
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21 pages, 1753 KB  
Review
V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities
by Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano and Anna Fassio
Cells 2024, 13(17), 1441; https://doi.org/10.3390/cells13171441 - 28 Aug 2024
Cited by 4 | Viewed by 4421
Abstract
Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H+ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels [...] Read more.
Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H+ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction. Full article
(This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration)
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24 pages, 8061 KB  
Article
TRIM44, a Novel Prognostic Marker, Supports the Survival of Proteasome-Resistant Multiple Myeloma Cells
by Trung Vu, Yuqin Wang, Annaliese Fowler, Anton Simieou and Nami McCarty
Cells 2024, 13(17), 1431; https://doi.org/10.3390/cells13171431 - 26 Aug 2024
Cited by 5 | Viewed by 2195
Abstract
TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a [...] Read more.
TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44’s significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target. Full article
(This article belongs to the Section Autophagy)
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29 pages, 2202 KB  
Review
Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging
by Gérald J. Prud’homme and Qinghua Wang
Cells 2024, 13(17), 1413; https://doi.org/10.3390/cells13171413 - 24 Aug 2024
Cited by 24 | Viewed by 9834
Abstract
The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have [...] Read more.
The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications. Full article
(This article belongs to the Section Tissues and Organs)
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20 pages, 4969 KB  
Article
The Expression of Toll-like Receptors in Cartilage Endplate Cells: A Role of Toll-like Receptor 2 in Pro-Inflammatory and Pro-Catabolic Gene Expression
by Tamara Mengis, Laura Bernhard, Andrea Nüesch, Irina Heggli, Nick Herger, Jan Devan, Roy Marcus, Christoph J. Laux, Florian Brunner, Mazda Farshad, Oliver Distler, Christine L. Le Maitre and Stefan Dudli
Cells 2024, 13(17), 1402; https://doi.org/10.3390/cells13171402 - 23 Aug 2024
Cited by 3 | Viewed by 2020
Abstract
Introduction: The vertebral cartilage endplate (CEP), crucial for intervertebral disc health, is prone to degeneration linked to chronic low back pain, disc degeneration, and Modic changes (MC). While it is known that disc cells express toll-like receptors (TLRs) that recognize pathogen- and damage-associated [...] Read more.
Introduction: The vertebral cartilage endplate (CEP), crucial for intervertebral disc health, is prone to degeneration linked to chronic low back pain, disc degeneration, and Modic changes (MC). While it is known that disc cells express toll-like receptors (TLRs) that recognize pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), it is unclear if CEP cells (CEPCs) share this trait. The CEP has a higher cell density than the disc, making CEPCs an important contributor. This study aimed to identify TLRs on CEPCs and their role in pro-inflammatory and catabolic gene expression. Methods: Gene expression of TLR1–10 was measured in human CEPs and expanded CEPCs using quantitative polymerase chain reaction. Additionally, surface TLR expression was measured in CEPs grouped into non-MC and MC. CEPCs were stimulated with tumor necrosis factor alpha, interleukin 1 beta, small-molecule TLR agonists, or the 30 kDa N-terminal fibronectin fragment. TLR2 signaling was inhibited with TL2-C29, and TLR2 protein expression was measured with flow cytometry. Results: Ex vivo analysis found all 10 TLRs expressed, while cultured CEPCs lost TLR8 and TLR9 expression. TLR2 expression was significantly increased in MC1 CEPCs, and its expression increased significantly after pro-inflammatory stimulation. Stimulation of the TLR2/6 heterodimer upregulated TLR2 protein expression. The TLR2/1 and TLR2/6 ligands upregulated pro-inflammatory genes and matrix metalloproteases (MMP1, MMP3, and MMP13), and TLR2 inhibition inhibited their upregulation. Endplate resorptive capacity of TLR2 activation was confirmed in a CEP explant model. Conclusions: The expression of TLR1–10 in CEPCs suggests that the CEP is susceptible to PAMP and DAMP stimulation. Enhanced TLR2 expression in MC1, and generally in CEPCs under inflammatory conditions, has pro-inflammatory and pro-catabolic effects, suggesting a potential role in disc degeneration and MC. Full article
(This article belongs to the Special Issue Cellular and Molecular Events in Intervertebral Disc Development, Homeostasis and Disease)
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16 pages, 2568 KB  
Review
Molecular Mechanisms of Autophagy Decline during Aging
by Shaun H. Y. Lim, Malene Hansen and Caroline Kumsta
Cells 2024, 13(16), 1364; https://doi.org/10.3390/cells13161364 - 16 Aug 2024
Cited by 15 | Viewed by 6342
Abstract
Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. [...] Read more.
Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy. Full article
(This article belongs to the Special Issue Autophagy Meets Aging 2025)
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14 pages, 5113 KB  
Article
Extracellular Vesicle Transplantation Is Beneficial for Acute Kidney Injury
by Amankeldi A. Salybekov, Shigeaki Okamura, Takayasu Ohtake, Sumi Hidaka, Takayuki Asahara and Shuzo Kobayashi
Cells 2024, 13(16), 1335; https://doi.org/10.3390/cells13161335 - 12 Aug 2024
Cited by 1 | Viewed by 1868
Abstract
Under vasculogenic conditioning, certain pro-inflammatory subsets within peripheral blood mononuclear cells (PBMCs) undergo phenotypic transformation into pro-regenerative types, such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells. These transformed cells are collectively termed regeneration-associated cells (RACs). In this study, we [...] Read more.
Under vasculogenic conditioning, certain pro-inflammatory subsets within peripheral blood mononuclear cells (PBMCs) undergo phenotypic transformation into pro-regenerative types, such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells. These transformed cells are collectively termed regeneration-associated cells (RACs). In this study, we aimed to investigate the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared with a vehicle-treated group in the context of renal ischemia-reperfusion injury (R-IRI). Human PBMCs were cultured with defined growth factor cocktails for seven days to harvest RACs. EV quantity and size were characterized by nanoparticle tracking analysis. Notably, the systemic injection of RACev significantly decreased serum creatinine and blood urine nitrogen at day three compared to the control group. Histologically, the treatment group showed less fibrosis in the cortex and medullary areas (p < 0.04 and p < 0.01) compared to the control group. The CD31 staining confirmed enhanced capillary densities in the treatment group compared to the control group (p < 0.003). These beneficial effects were accompanied by angiogenesis, anti-fibrosis, anti-inflammation, and anti-apoptosis RACev miR delivery to ischemic injury to control inflammatory, endothelial mesenchymal transition, and hypoxia pathways. In vivo bioluminescence analysis demonstrated a preferential accumulation of RACev in the IR-injured kidney. The systemic transplantation of RACev beneficially restored kidney function by protecting from tissue fibrosis and through anti-inflammation, angiogenesis, and anti-apoptosis miR delivery to the ischemic tissue. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Tissue Repair and Regeneration)
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16 pages, 1262 KB  
Review
Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance
by Young Keun Hwang, Dong-Hun Lee, Eun Chae Lee and Jae Sang Oh
Cells 2024, 13(16), 1332; https://doi.org/10.3390/cells13161332 - 11 Aug 2024
Cited by 10 | Viewed by 3776
Abstract
Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling [...] Read more.
Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival. Full article
(This article belongs to the Section Autophagy)
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24 pages, 663 KB  
Review
In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes
by Candida Fasano, Martina Lepore Signorile, Katia De Marco, Giovanna Forte, Vittoria Disciglio, Paola Sanese, Valentina Grossi and Cristiano Simone
Cells 2024, 13(16), 1314; https://doi.org/10.3390/cells13161314 - 6 Aug 2024
Cited by 5 | Viewed by 2633
Abstract
Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis [...] Read more.
Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes. Full article
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12 pages, 1822 KB  
Article
Synthetic mRNAs Containing Minimalistic Untranslated Regions Are Highly Functional In Vitro and In Vivo
by Shahab Mamaghani, Rocco Roberto Penna, Julia Frei, Conrad Wyss, Mark Mellett, Thomas Look, Tobias Weiss, Emmanuella Guenova, Thomas M. Kündig, Severin Lauchli and Steve Pascolo
Cells 2024, 13(15), 1242; https://doi.org/10.3390/cells13151242 - 24 Jul 2024
Cited by 8 | Viewed by 4709
Abstract
Synthetic mRNA produced by in vitro transcription (ivt mRNA) is the active pharmaceutical ingredient of approved anti-COVID-19 vaccines and of many drugs under development. Such synthetic mRNA typically contains several hundred bases of non-coding “untranslated” regions (UTRs) that are involved in the stabilization [...] Read more.
Synthetic mRNA produced by in vitro transcription (ivt mRNA) is the active pharmaceutical ingredient of approved anti-COVID-19 vaccines and of many drugs under development. Such synthetic mRNA typically contains several hundred bases of non-coding “untranslated” regions (UTRs) that are involved in the stabilization and translation of the mRNA. However, UTRs are often complex structures, which may complicate the entire production process. To eliminate this obstacle, we managed to reduce the total amount of nucleotides in the UTRs to only four bases. In this way, we generate minimal ivt mRNA (“minRNA”), which is less complex than the usual optimized ivt mRNAs that are contained, for example, in approved vaccines. We have compared the efficacy of minRNA to common augmented mRNAs (with UTRs of globin genes or those included in licensed vaccines) in vivo and in vitro and could demonstrate equivalent functionalities. Our minimal mRNA design will facilitate the further development and implementation of ivt mRNA-based vaccines and therapies. Full article
(This article belongs to the Section Cell and Gene Therapy)
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32 pages, 1003 KB  
Review
Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury
by Michał Szymoniuk, Jakub Litak, Leon Sakwa, Aleksandra Dryla, Wojciech Zezuliński, Wojciech Czyżewski, Piotr Kamieniak and Tomasz Blicharski
Cells 2023, 12(1), 120; https://doi.org/10.3390/cells12010120 - 28 Dec 2022
Cited by 29 | Viewed by 6983
Abstract
Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number [...] Read more.
Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number of patients experience a complete recovery. Current standard treatment modalities of the SCI aim to prevent secondary injury and provide limited recovery of lost neurological functions. Stem Cell Therapy (SCT) represents an emerging treatment approach using the differentiation, paracrine, and self-renewal capabilities of stem cells to regenerate the injured spinal cord. To date, multipotent stem cells including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) represent the most investigated types of stem cells for the treatment of SCI in preclinical and clinical studies. The microenvironment of SCI has a significant impact on the survival, proliferation, and differentiation of transplanted stem cells. Therefore, a deep understanding of the pathophysiology of SCI and molecular mechanisms through which stem cells act may help improve the treatment efficacy of SCT and find new therapeutic approaches such as stem-cell-derived exosomes, gene-modified stem cells, scaffolds, and nanomaterials. In this literature review, the pathogenesis of SCI and molecular mechanisms of action of multipotent stem cells including MSCs, NSCs, and HSCs are comprehensively described. Moreover, the clinical efficacy of multipotent stem cells in SCI treatment, an optimal protocol of stem cell administration, and recent therapeutic approaches based on or combined with SCT are also discussed. Full article
(This article belongs to the Special Issue Neural Repair of the Central Nervous System: Stem Cells and Other Approaches)
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17 pages, 3144 KB  
Article
Advanced Maternal Age Differentially Affects Embryonic Tissues with the Most Severe Impact on the Developing Brain
by Caroline Kokorudz, Bethany N. Radford, Wendy Dean and Myriam Hemberger
Cells 2023, 12(1), 76; https://doi.org/10.3390/cells12010076 - 24 Dec 2022
Cited by 10 | Viewed by 3647
Abstract
Advanced maternal age (AMA) poses the single greatest risk to a successful pregnancy. Apart from the impact of AMA on oocyte fitness, aged female mice often display defects in normal placentation. Placental defects in turn are tightly correlated with brain and cardiovascular abnormalities. [...] Read more.
Advanced maternal age (AMA) poses the single greatest risk to a successful pregnancy. Apart from the impact of AMA on oocyte fitness, aged female mice often display defects in normal placentation. Placental defects in turn are tightly correlated with brain and cardiovascular abnormalities. It therefore follows that placenta, brain and heart development may be particularly susceptible to the impact of AMA. In the current study, we compared global transcriptomes of placentas, brains, hearts, and facial prominences from mid-gestation mouse conceptuses developed in young control (7–13 wks) and aging (43–50 wks) females. We find that AMA increases transcriptional heterogeneity in all tissues, but particularly in fetal brain. Importantly, even overtly normally developed embryos from older females display dramatic expression changes in neurodevelopmental genes. These transcriptomic alterations in the brain are likely induced by defects in placental development. Using trophoblast stem cells (TSCs) as a model, we show that exposure to aging uterine stromal cell-conditioned medium interferes with normal TSC proliferation and causes precocious differentiation, recapitulating many of the defects observed in placentas from aged females. These data highlight the increased risk of AMA on reproductive outcome, with neurodevelopment being the most sensitive to such early perturbations and with potential for lifelong impact. Full article
(This article belongs to the Section Reproductive Cells and Development)
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20 pages, 3401 KB  
Article
Impact of Mitochondrial A3243G Heteroplasmy on Mitochondrial Bioenergetics and Dynamics of Directly Reprogrammed MELAS Neurons
by Dar-Shong Lin, Yu-Wen Huang, Che-Sheng Ho, Tung-Sun Huang, Tsung-Han Lee, Tsu-Yen Wu, Zon-Darr Huang and Tuan-Jen Wang
Cells 2023, 12(1), 15; https://doi.org/10.3390/cells12010015 - 21 Dec 2022
Cited by 11 | Viewed by 3334
Abstract
The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper [...] Read more.
The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (>95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Dynamics and Neurodegeneration)
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28 pages, 5418 KB  
Article
Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice
by Henna Jäntti, Minna Oksanen, Pinja Kettunen, Stella Manta, Lionel Mouledous, Hennariikka Koivisto, Johanna Ruuth, Kalevi Trontti, Hiramani Dhungana, Meike Keuters, Isabelle Weert, Marja Koskuvi, Iiris Hovatta, Anni-Maija Linden, Claire Rampon, Tarja Malm, Heikki Tanila, Jari Koistinaho and Taisia Rolova
Cells 2022, 11(24), 4116; https://doi.org/10.3390/cells11244116 - 18 Dec 2022
Cited by 3 | Viewed by 4401
Abstract
The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell [...] Read more.
The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors. Full article
(This article belongs to the Special Issue Glial Cells in Synaptic Plasticity)
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13 pages, 2045 KB  
Article
Tumor Growth Remains Refractory to Myc Ablation in Host Macrophages
by Riley J. Morrow, Amr H. Allam, Josh Konecnik, David Baloyan, Christine Dijkstra, Moritz F. Eissmann, Saumya P. Jacob, Megan O’Brien, Ashleigh R. Poh and Matthias Ernst
Cells 2022, 11(24), 4104; https://doi.org/10.3390/cells11244104 - 17 Dec 2022
Viewed by 2594
Abstract
Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, [...] Read more.
Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, including macrophages and other myeloid cells. Here, we benchmark Myc inactivation in tumor cells against the contribution of its expression in myeloid cells of murine hosts that harbor endogenous or allograft tumors. Surprisingly, we observe that LysMCre-mediated Myc ablation in host macrophages does not attenuate tumor growth regardless of immunogenicity, the cellular origin of the tumor, the site it develops, or the stage along the tumor progression cascade. Likewise, we find no evidence for Myc ablation to revert or antagonize the polarization of alternatively activated immunosuppressive macrophages. Thus, we surmise that systemic targeting of Myc activity may confer therapeutic benefits primarily through limiting Myc activity in tumor cells rather than reinvigorating the anti-tumor activity of macrophages. Full article
(This article belongs to the Special Issue MYC Signaling in Cancer)
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15 pages, 1461 KB  
Article
Pre-Transplant Prediction of Acute Graft-versus-Host Disease Using the Gut Microbiome
by Ramtin Zargari Marandi, Mette Jørgensen, Emma Elizabeth Ilett, Jens Christian Nørgaard, Marc Noguera-Julian, Roger Paredes, Jens D. Lundgren, Henrik Sengeløv and Cameron Ross MacPherson
Cells 2022, 11(24), 4089; https://doi.org/10.3390/cells11244089 - 16 Dec 2022
Cited by 7 | Viewed by 4180
Abstract
Gut microbiota is thought to influence host responses to allogeneic hematopoietic stem cell transplantation (aHSCT). Recent evidence points to this post-transplant for acute graft-versus-host disease (aGvHD). We asked whether any such association might be found pre-transplant and conducted a metagenome-wide association study (MWAS) [...] Read more.
Gut microbiota is thought to influence host responses to allogeneic hematopoietic stem cell transplantation (aHSCT). Recent evidence points to this post-transplant for acute graft-versus-host disease (aGvHD). We asked whether any such association might be found pre-transplant and conducted a metagenome-wide association study (MWAS) to explore. Microbial abundance profiles were estimated using ensembles of Kaiju, Kraken2, and DeepMicrobes calls followed by dimensionality reduction. The area under the curve (AUC) was used to evaluate classification of the samples (aGvHD vs. none) using an elastic net to test the relevance of metagenomic data. Clinical data included the underlying disease (leukemia vs. other hematological malignancies), recipient age, and sex. Among 172 aHSCT patients of whom 42 developed aGVHD post transplantation, a total of 181 pre-transplant tool samples were analyzed. The top performing model predicting risk of aGVHD included a reduced species profile (AUC = 0.672). Beta diversity (37% in Jaccard’s Nestedness by mean fold change, p < 0.05) was lower in those developing aGvHD. Ten bacterial species including Prevotella and Eggerthella genera were consistently found to associate with aGvHD in indicator species analysis, as well as relief and impurity-based algorithms. The findings support the hypothesis on potential associations between gut microbiota and aGvHD based on a data-driven approach to MWAS. This highlights the need and relevance of routine stool collection for the discovery of novel biomarkers. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Microenvironment)
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21 pages, 27931 KB  
Article
Loss of Pex1 in Inner Ear Hair Cells Contributes to Cochlear Synaptopathy and Hearing Loss
by Stephanie A. Mauriac, Thibault Peineau, Aamir Zuberi, Cathleen Lutz and Gwénaëlle S. G. Géléoc
Cells 2022, 11(24), 3982; https://doi.org/10.3390/cells11243982 - 9 Dec 2022
Cited by 4 | Viewed by 3466
Abstract
Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause [...] Read more.
Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause PBD-ZSD with ~70% of patients harboring mutations in PEX1. Limited research has focused on the impact of peroxisomal disorders on auditory function. As sensory hair cells are particularly vulnerable to metabolic changes, we hypothesize that mutations in PEX1 lead to oxidative stress affecting hair cells of the inner ear, subsequently resulting in hair cell degeneration and hearing loss. Global deletion of the Pex1 gene is neonatal lethal in mice, impairing any postnatal studies. To overcome this limitation, we created conditional knockout mice (cKO) using Gfi1Creor VGlut3Cre expressing mice crossed to floxed Pex1 mice to allow for selective deletion of Pex1 in the hair cells of the inner ear. We find that Pex1 excision in inner hair cells (IHCs) leads to progressive hearing loss associated with significant decrease in auditory brainstem responses (ABR), specifically ABR wave I amplitude, indicative of synaptic defects. Analysis of IHC synapses in cKO mice reveals a decrease in ribbon synapse volume and functional alterations in exocytosis. Concomitantly, we observe a decrease in peroxisomal number, indicative of oxidative stress imbalance. Taken together, these results suggest a critical function of Pex1 in development and maturation of IHC-spiral ganglion synapses and auditory function. Full article
(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)
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22 pages, 1310 KB  
Review
The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology
by Isaure Vanmeerbeek, Jannes Govaerts, Raquel S. Laureano, Jenny Sprooten, Stefan Naulaerts, Daniel M. Borras, Damya Laoui, Massimiliano Mazzone, Jo A. Van Ginderachter and Abhishek D. Garg
Cells 2022, 11(23), 3890; https://doi.org/10.3390/cells11233890 - 2 Dec 2022
Cited by 18 | Viewed by 7813
Abstract
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer [...] Read more.
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies. Full article
(This article belongs to the Special Issue Immunogenic Cell Stress and Death)
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18 pages, 1837 KB  
Review
A Review on Autophagy in Orofacial Neuropathic Pain
by Mayank Shrivastava and Liang Ye
Cells 2022, 11(23), 3842; https://doi.org/10.3390/cells11233842 - 30 Nov 2022
Cited by 7 | Viewed by 3285
Abstract
Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of [...] Read more.
Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of understanding of the mechanisms underlying the etiology and pathogenesis. In the last few decades, researchers have developed diagnostic criteria, questionnaires, and clinical assessment methods for the diagnosis of orofacial neuropathic pain. Recently, researchers have observed the role of autophagy in neuronal dysfunction as well as in the modulation of neuropathic pain. On this basis, in the present review, we highlight the characteristics, classification, and clinical assessment of orofacial neuropathic pain. Additionally, we introduce autophagy and its potential role in the modulation of orofacial neuropathic pain, along with a brief overview of the pathogenesis, which in future may reveal new possible targets for treating this condition. Full article
(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)
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17 pages, 3633 KB  
Article
High-Content RNAi Phenotypic Screening Unveils the Involvement of Human Ubiquitin-Related Enzymes in Late Cytokinesis
by Mikaël Boullé, Laurianne Davignon, Keïs Nabhane Saïd Halidi, Salomé Guez, Emilie Giraud, Marcel Hollenstein and Fabrice Agou
Cells 2022, 11(23), 3862; https://doi.org/10.3390/cells11233862 - 30 Nov 2022
Cited by 1 | Viewed by 2894
Abstract
CEP55 is a central regulator of late cytokinesis and is overexpressed in numerous cancers. Its post-translationally controlled recruitment to the midbody is crucial to the structural coordination of the abscission sequence. Our recent evidence that CEP55 contains two ubiquitin-binding domains was the first [...] Read more.
CEP55 is a central regulator of late cytokinesis and is overexpressed in numerous cancers. Its post-translationally controlled recruitment to the midbody is crucial to the structural coordination of the abscission sequence. Our recent evidence that CEP55 contains two ubiquitin-binding domains was the first structural and functional link between ubiquitin signaling and ESCRT-mediated severing of the intercellular bridge. So far, high-content screens focusing on cytokinesis have used multinucleation as the endpoint readout. Here, we report an automated image-based detection method of intercellular bridges, which we applied to further our understanding of late cytokinetic signaling by performing an RNAi screen of ubiquitin ligases and deubiquitinases. A secondary validation confirmed four candidate genes, i.e., LNX2, NEURL, UCHL1 and RNF157, whose downregulation variably affects interconnected phenotypes related to CEP55 and its UBDs, as follows: decreased recruitment of CEP55 to the midbody, increased number of midbody remnants per cell, and increased frequency of intercellular bridges or multinucleation events. This brings into question the Notch-dependent or independent contributions of LNX2 and NEURL proteins to late cytokinesis. Similarly, the role of UCHL1 in autophagy could link its function with the fate of midbody remnants. Beyond the biological interest, this high-content screening approach could also be used to isolate anticancer drugs that act by impairing cytokinesis and CEP55 functions. Full article
(This article belongs to the Special Issue Molecular Factors and Mechanisms Involved in Cytokinesis II)
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17 pages, 7647 KB  
Article
Dynamic Changes in the Extracellular Matrix in Primary, Metastatic, and Recurrent Ovarian Cancers
by Arkadiusz Gertych, Ann E. Walts, Keyi Cheng, Manyun Liu, Joshi John, Jenny Lester, Beth Y. Karlan and Sandra Orsulic
Cells 2022, 11(23), 3769; https://doi.org/10.3390/cells11233769 - 25 Nov 2022
Cited by 11 | Viewed by 3469
Abstract
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational [...] Read more.
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1+ CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8+ T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8+ T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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31 pages, 3152 KB  
Review
Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy
by Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim and Han-Jung Chae
Cells 2022, 11(23), 3773; https://doi.org/10.3390/cells11233773 - 25 Nov 2022
Cited by 8 | Viewed by 4888
Abstract
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged [...] Read more.
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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13 pages, 2027 KB  
Article
4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression
by Kazuki Hasegawa, Ryo Saga, Kentaro Ohuchi, Yoshikazu Kuwahara, Kazuo Tomita, Kazuhiko Okumura, Tomoaki Sato, Manabu Fukumoto, Eichi Tsuruga and Yoichiro Hosokawa
Cells 2022, 11(23), 3780; https://doi.org/10.3390/cells11233780 - 25 Nov 2022
Cited by 7 | Viewed by 2435
Abstract
Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of [...] Read more.
Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of 4-MU with X-ray irradiation enhanced radiosensitization. However, an effective sensitizer for radioresistant (RR) cells is yet to be established, and it is unknown whether 4-MU exerts radiosensitizing effects on RR cells. We investigated the radiosensitizing effects of 4-MU in RR cell models. This study revealed that 4-MU enhanced intracellular oxidative stress and suppressed the expression of cluster-of-differentiation (CD)-44 and cancer stem cell (CSC)-like phenotypes. Interestingly, eliminating extracellular HA using HA-degrading enzymes did not cause radiosensitization, whereas HAS3 knockdown using siRNA showed similar effects as 4-MU treatment. These results suggest that 4-MU treatment enhances radiosensitization of RR cells through enhancing oxidative stress and suppressing the CSC-like phenotype. Furthermore, the radiosensitizing mechanisms of 4-MU may involve HAS3 or intracellular HA synthesized by HAS3. Full article
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15 pages, 7082 KB  
Article
Low-Dose rIL-15 Protects from Nephrotoxic Serum Nephritis via CD8+ T Cells
by Agnes A. Mooslechner, Max Schuller, Katharina Artinger, Alexander H. Kirsch, Corinna Schabhüttl, Philipp Eller, Alexander R. Rosenkranz and Kathrin Eller
Cells 2022, 11(22), 3656; https://doi.org/10.3390/cells11223656 - 18 Nov 2022
Cited by 3 | Viewed by 3117
Abstract
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated [...] Read more.
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated kidney disease since it has proven to be tubular-protective before. Therefore, we set out to test the potential of low-dose rIL-15 treatment in a mouse model of nephrotoxic serum nephritis (NTS), mimicking immune complex-driven GN in humans. A single low-dose treatment with rIL-15 ameliorated NTS, reflected by reduced albuminuria, less tissue scarring, fewer myeloid cells in the kidney, and improved tubular epithelial cell survival. In addition, CD8+ T cells, a primary target of IL-15, showed altered gene expression and function corresponding with less cytotoxicity mediated by rIL-15. With the use of transgenic knock-out mice, antibody depletion, and adoptive cell transfer studies, we here show that the beneficial effects of rIL-15 treatment in NTS depended on CD8+ T cells, suggesting a pivotal role for them in the underlying mechanism. Our findings add to existing evidence of the association of IL-15 with kidney health and imply a potential for low-dose rIL-15 immunotherapies in GN. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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42 pages, 1992 KB  
Review
Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology
by Aleš Cvekl and Michael John Camerino
Cells 2022, 11(21), 3516; https://doi.org/10.3390/cells11213516 - 6 Nov 2022
Cited by 13 | Viewed by 5154
Abstract
In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids [...] Read more.
In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids and specific ocular tissues from pluripotent stem cells has provided invaluable insights into the formation of lineage-committed progenitor cell populations, signal transduction pathways, and self-organization principles. This review provides a comprehensive summary of recent advances in generation of adenohypophyseal, olfactory, and lens placodes, lens progenitor cells and three-dimensional (3D) primitive lenses, “lentoid bodies”, and “micro-lenses”. These cells are produced alone or “community-grown” with other ocular tissues. Lentoid bodies/micro-lenses generated from human patients carrying mutations in crystallin genes demonstrate proof-of-principle that these cells are suitable for mechanistic studies of cataractogenesis. Taken together, current and emerging advanced in vitro differentiation methods pave the road to understand molecular mechanisms of cataract formation caused by the entire spectrum of mutations in DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, and HSF4, individual crystallins, and other genes such as BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, and TDRD7 represented in human cataract patients. Full article
(This article belongs to the Special Issue New Advances in Lens Biology and Pathology)
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15 pages, 2879 KB  
Article
The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression
by Wiebke Breternitz, Friedrich Sandkühler, Frauke Grohmann, Jochen Hampe, Mario Brosch, Alexander Herrmann, Clemens Schafmayer, Christian Meinhardt, Stefan Schreiber, Alexander Arlt and Claudia Geismann
Cells 2022, 11(21), 3504; https://doi.org/10.3390/cells11213504 - 4 Nov 2022
Cited by 5 | Viewed by 3414
Abstract
Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric [...] Read more.
Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric surgery, we recently demonstrated the strong enrichment of differentially methylated heat shock factor 1 (HSF1) binding sites (>400-fold) in the process of liver remodeling, indicating a crucial role of HSF1 in modulating central aspects of NAFLD pathogenesis. Using cellular models of NAFLD, we were able to show that HSF1 is activated during fat accumulation in hepatocytes, mimicking conditions in patients before bariatric surgery. This induction was abolished by starving the cells, mimicking the situation after bariatric surgery. Regarding this connection, carnitine palmitoyltransferase 1 isoform A (CTP1a), a central regulator of lipid beta-oxidation, was identified as a HSF1 target gene by promoter analysis and HSF1 knockdown experiments. Finally, pharmacological activation of HSF1 through celastrol reduced fat accumulation in the cells in a HSF1-dependent manner. In conclusion, we were able to confirm the relevance of HSF1 activity and described a functional HSF1-CPT1a pathway in NAFLD pathogenesis. Full article
(This article belongs to the Special Issue Metabolic Regulation: Cell Growth and Proliferation)
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19 pages, 1416 KB  
Review
A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration
by Hanna Heloterä and Kai Kaarniranta
Cells 2022, 11(21), 3453; https://doi.org/10.3390/cells11213453 - 1 Nov 2022
Cited by 64 | Viewed by 8449
Abstract
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD (nAMD). Dry AMD is the most prevalent form (80–90%) of AMD cases. Neovascular AMD (10–20% of AMD cases) is treated with monthly or more sparsely given intravitreal anti-vascular endothelial growth factor inhibitors, but unfortunately, not all patients respond to the current treatments. A clinical hallmark of nAMD is choroidal neovascularization. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Cellular damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to advanced geographic atrophy and/or choroidal neovascularization and fibrosis. Currently, it is not fully known why different AMD phenotypes develop. In this review, we connect angiogenesis and inflammatory regulators in the development of nAMD and discuss therapy challenges and hopes. Full article
(This article belongs to the Special Issue The Role of Inflammation in AMD (Multifactorial Age-Related Macular Degeneration))
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27 pages, 3449 KB  
Review
Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications
by Caroline McLaughlin, Pallab Datta, Yogendra P. Singh, Alexis Lo, Summer Horchler, Irina A. Elcheva, Ibrahim T. Ozbolat, Dino J. Ravnic and Srinivas V. Koduru
Cells 2022, 11(21), 3366; https://doi.org/10.3390/cells11213366 - 25 Oct 2022
Cited by 29 | Viewed by 6064
Abstract
Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth [...] Read more.
Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC–EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles)
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11 pages, 625 KB  
Review
Morbidity and Mortality of Neutropenic Patients in Visceral Surgery: A Narrative Review
by Ann-Kathrin Lederer, Fabian Bartsch, Markus Moehler, Peter Gaßmann and Hauke Lang
Cells 2022, 11(20), 3314; https://doi.org/10.3390/cells11203314 - 21 Oct 2022
Cited by 6 | Viewed by 3610
Abstract
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are [...] Read more.
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell–cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality. Full article
(This article belongs to the Collection Emerging Roles of Neutrophil in Inflammation and Immunity)
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27 pages, 7126 KB  
Article
Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival
by Dorothee Brech, Anna S. Herbstritt, Sarah Diederich, Tobias Straub, Evangelos Kokolakis, Martin Irmler, Johannes Beckers, Florian A. Büttner, Elke Schaeffeler, Stefan Winter, Matthias Schwab, Peter J. Nelson and Elfriede Noessner
Cells 2022, 11(20), 3289; https://doi.org/10.3390/cells11203289 - 19 Oct 2022
Cited by 10 | Viewed by 5002
Abstract
Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, [...] Read more.
Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, where their presence is generally associated with poor patient prognosis. These cells are highly adaptable and plastic, and can be modulated to perform desired functions such as antitumor activity, if key programming molecules can be identified. Human clear cell renal cell carcinoma (ccRCC) is considered immunogenic; yet checkpoint blockades that target T cell dysfunction have shown limited clinical efficacy, suggesting additional layers of immunoinhibition. We previously described “enriched-in-renal cell carcinoma” (erc) DCs that were often found in tight contact with dysfunctional T cells. Using transcriptional profiling and flow cytometry, we describe here that ercDCs represent a mosaic cell type within the macrophage continuum co-expressing M1 and M2 markers. The polarization state reflects tissue-specific signals that are characteristic of RCC and renal tissue homeostasis. ErcDCs are tissue-resident with increasing prevalence related to tumor grade. Accordingly, a high ercDC score predicted poor patient survival. Within the profile, therapeutic targets (VSIG4, NRP1, GPNMB) were identified with promise to improve immunotherapy. Full article
(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)
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27 pages, 893 KB  
Review
The Extracellular Matrix and Neuroblastoma Cell Communication—A Complex Interplay and Its Therapeutic Implications
by Irena Horwacik
Cells 2022, 11(19), 3172; https://doi.org/10.3390/cells11193172 - 10 Oct 2022
Cited by 16 | Viewed by 4182
Abstract
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients [...] Read more.
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients call for more research to further inter-relate treatment and molecular features of the disease. In this regard, it is well established that in the tumor microenvironment (TME), malignant cells are engaged in complex and dynamic interactions with the extracellular matrix (ECM) and stromal cells. The ECM can be a source of both pro- and anti-tumorigenic factors to regulate tumor cell fate, such as survival, proliferation, and resistance to therapy. Moreover, the ECM composition, organization, and resulting signaling networks are vastly remodeled during tumor progression and metastasis. This review mainly focuses on the molecular mechanisms and effects of interactions of selected ECM components with their receptors on neuroblastoma cells. Additionally, it describes roles of enzymes modifying and degrading ECM in NB. Finally, the article gives examples on how the knowledge is exploited for prognosis and to yield new treatment options for NB patients. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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10 pages, 935 KB  
Hypothesis
AIRE in Male Fertility: A New Hypothesis
by Jana Petrusová, Jasper Manning and Dominik Filipp
Cells 2022, 11(19), 3168; https://doi.org/10.3390/cells11193168 - 9 Oct 2022
Cited by 1 | Viewed by 2413
Abstract
Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied [...] Read more.
Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied in the context of central tolerance functioning as a nuclear transcription modulator, responsible for the expression of tissue-restricted antigens in specialized thymic cells that prevent autoimmunity. While its expression in the testes remains enigmatic, we recently observed that sterility in mice correlates with the absence of Aire in the testes, regardless of the deficient expression in medullary thymic epithelial cells or cells of the hematopoietic system. By assessing the Aire transcript levels, we discovered that Sertoli cells are the exclusive source of Aire in the testes, where it most likely plays a non-immune role, suggesting an unknown mechanism by which testicular Aire regulates fertility. Here, we discuss these results in the context of previous reports which have suggested that infertility observed in Aire deficient mice is of an autoimmune aetiology. We present an alternative point of view for the role of Aire in testes in respect to fertility altering the perspective of how Aire’s function in the testes is currently perceived. Full article
(This article belongs to the Section Reproductive Cells and Development)
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11 pages, 1632 KB  
Article
Characterization of the Aquaporin-9 Inhibitor RG100204 In Vitro and in db/db Mice
by Marilina Florio, Angelica Engfors, Patrizia Gena, Jessica Larsson, Alessandro Massaro, Stella Timpka, Martina Kvist Reimer, Per Kjellbom, Eric Beitz, Urban Johanson, Michael Rützler and Giuseppe Calamita
Cells 2022, 11(19), 3118; https://doi.org/10.3390/cells11193118 - 4 Oct 2022
Cited by 9 | Viewed by 2972
Abstract
Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas [...] Read more.
Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas that permit inhibitor binding. The few AQP9 inhibitor molecules described to date were not suitable for in vivo experiments. We now describe the characterization of a new small molecule AQP9 inhibitor, RG100204 in cell-based calcein-quenching assays, and by stopped-flow light-scattering recordings of AQP9 permeability in proteoliposomes. Moreover, we investigated the effects of RG100204 on glycerol metabolism in mice. In cell-based assays, RG100204 blocked AQP9 water permeability and glycerol permeability with similar, high potency (~5 × 10−8 M). AQP9 channel blocking by RG100204 was confirmed in proteoliposomes. After oral gavage of db/db mice with RG100204, a dose-dependent elevation of plasma glycerol was observed. A blood glucose-lowering effect was not statistically significant. These experiments establish RG100204 as a direct blocker of the AQP9 channel, and suggest its use as an experimental tool for in vivo experiments on AQP9 function. Full article
(This article belongs to the Section Cellular Metabolism)
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17 pages, 5246 KB  
Article
Proteomic and Phosphoproteomic Profiling Reveals the Oncogenic Role of Protein Kinase D Family Kinases in Cholangiocarcinoma
by Yun Lu, Xiangyu Li, Kai Zhao, Yuanxin Shi, Zhengdong Deng, Wei Yao and Jianming Wang
Cells 2022, 11(19), 3088; https://doi.org/10.3390/cells11193088 - 30 Sep 2022
Cited by 7 | Viewed by 3157
Abstract
Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from [...] Read more.
Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from patients with CCA and predicted eleven PKs high-potentially related to CCA with a comprehensive inference of the functional protein kinases (PKs) (CifPK) pipeline. Besides the two known CCA-associated PKs, we screened the remaining candidates and uncovered five PKs as novel regulators in CCA. Specifically, the protein kinase D (PKD) family members, including PRKD1, PRKD2, and PRKD3, were identified as critical regulators in CCA. Moreover, the pan-inhibitor of the PKD family, 1-naphthyl PP1 (1-NA-PP1), was validated as a potent agent for inhibiting the proliferation, migration, and invasion ability of CCA cells. This study reveals new PKs associated with CCA and suggests PRKD kinases as novel treatment targets for CCA. Full article
(This article belongs to the Special Issue New Insights into Proteomics and Post-translational Modification of Proteins)
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15 pages, 2006 KB  
Review
The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis
by Elisa D’Alessandro, Joris Winters, Frans A. van Nieuwenhoven, Ulrich Schotten and Sander Verheule
Cells 2022, 11(19), 2963; https://doi.org/10.3390/cells11192963 - 22 Sep 2022
Cited by 16 | Viewed by 3101
Abstract
Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy [...] Read more.
Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability. Full article
(This article belongs to the Special Issue Molecular Biology of Atrial Myocardium)
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14 pages, 876 KB  
Review
Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State
by Abdiasis M. Hussein, Nanditaa Balachandar, Julie Mathieu and Hannele Ruohola-Baker
Cells 2022, 11(19), 2929; https://doi.org/10.3390/cells11192929 - 20 Sep 2022
Cited by 19 | Viewed by 8095
Abstract
Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of [...] Read more.
Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of newborns. Diapause arrests the embryo at the blastocyst stage, delaying the post-implantation development of the embryo. This months-long quiescence is reversible, in contrast to senescence that occurs in aging stem cells. Recent studies have revealed critical regulators of diapause. These findings are important since defects in the diapause state can cause a lack of regeneration and control of normal growth. Controlling this state may also have therapeutic applications since recent findings suggest that radiation and chemotherapy may lead some cancer cells to a protective diapause-like, reversible state. Interestingly, recent studies have shown the metabolic regulation of epigenetic modifications and the role of microRNAs in embryonic diapause. In this review, we discuss the molecular mechanism of diapause induction. Full article
(This article belongs to the Collection Exclusive Papers from Editorial Board Members and Invited Scholars in Cells)
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20 pages, 3466 KB  
Article
Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies
by Lei Wang, Lieke E. J. van Iersel, Charlotte E. Pelgrim, Jingyi Lu, Ingrid van Ark, Thea Leusink-Muis, Harry R. Gosker, Ramon C. J. Langen, Annemie M. W. J. Schols, Josep M. Argilés, Ardy van Helvoort, Aletta D. Kraneveld, Johan Garssen, Paul A. J. Henricks, Gert Folkerts and Saskia Braber
Cells 2022, 11(18), 2893; https://doi.org/10.3390/cells11182893 - 16 Sep 2022
Cited by 19 | Viewed by 6544
Abstract
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro [...] Read more.
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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15 pages, 3542 KB  
Article
Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit
by Violeta Stojanovska, Susanne Arnold, Mario Bauer, Hermann Voss, Stefan Fest and Ana Claudia Zenclussen
Cells 2022, 11(18), 2884; https://doi.org/10.3390/cells11182884 - 15 Sep 2022
Cited by 17 | Viewed by 4412
Abstract
It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized [...] Read more.
It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized three different 3D cultures (e.g., spheroids) derived from trophoblast cell lines and studied their functionality in comparison to primary fetal trophoblasts and placental tissue. The spheroid growth rates of JEG3, BeWo and HTR8/SVneo cell lines were similar among each other and were significantly larger in comparison to primary trophoblast spheroids. All spheroids exhibited migratory properties and shortest distances were registered for JEG3 spheroids. Even though all spheroids displayed invasive capabilities, only the invasive features of HTR8/SVneo spheroids resulted in specific branching. This was in agreement with the invasive properties of the spheroids obtained from primary trophoblasts. Human chorionic gonadotropin production was highest in JEG3 spheroids and only increased when stimulated with cAMP and forskolin in BeWo, but not HTR8/SVneo spheroids. The gene expression analysis confirmed that 3D trophoblast cell cultures and especially HTR8/SVneo spheroids showed considerable similarities with the gene expression profile of primary placental tissue. This study offers a broad characterization of 3D trophoblast spheroids that, in turn, can help in selecting the best model depending on the scientific question that needs to be answered. Full article
(This article belongs to the Special Issue Placental Development in Health and Disease)
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23 pages, 4047 KB  
Article
The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism
by Sonia Spinelli, Lucrezia Guida, Tiziana Vigliarolo, Mario Passalacqua, Giulia Begani, Mirko Magnone, Laura Sturla, Andrea Benzi, Pietro Ameri, Edoardo Lazzarini, Claudia Bearzi, Roberto Rizzi and Elena Zocchi
Cells 2022, 11(18), 2888; https://doi.org/10.3390/cells11182888 - 15 Sep 2022
Cited by 20 | Viewed by 4466
Abstract
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We [...] Read more.
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia. Full article
(This article belongs to the Collection Regulation of Cell Function by AMPK and Sirtuins: From Basic Research to Disease and Aging)
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14 pages, 2204 KB  
Article
Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy
by Ya-Ru Miao, Chun-Jie Liu, Hui Hu, Mei Yang and An-Yuan Guo
Cells 2022, 11(18), 2802; https://doi.org/10.3390/cells11182802 - 8 Sep 2022
Cited by 8 | Viewed by 3283
Abstract
Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response [...] Read more.
Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74–0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research. Full article
(This article belongs to the Special Issue Cutting Edge in Bioinformatics of Cancer Immunotherapy)
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