Next Issue
Volume 13, August-1
Previous Issue
Volume 13, July-1
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
9.9
5.1
Journals
Cells
Volume 13
Issue 14
share announcement

Cells, Volume 13, Issue 14 (July-2 2024) – 66 articles

Cover Story (view full-size image): Bipolar disorder (BP) is a serious, recurrent mood disorder that is characterized by alternating episodes of mania and depression. Evidence suggests that changes in the development and function of several neural subtypes contribute to these shifts in moods. We derived stem cells from patients with BP who had a single-nucleotide polymorphism, rs1006737, in CACNA1C. We generated control (C), BP, and isogenic human induced pluripotent stem cell (iPSC) lines and differentiated them into GABAergic neurons, harvesting cells at sequential stages of the differentiation. BP GABAergic neurons differ in ion channel expression and neuronal function during their development compared to C. Understanding the developmental and functional differences in BP GABAergic neurons may help identify novel therapeutic targets to treat bipolar disorder. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
17 pages, 2133 KiB  
Review
Novel Technologies to Address the Lower Motor Neuron Injury and Augment Reconstruction in Spinal Cord Injury
by Stanley F. Bazarek, Matthias J. Krenn, Sameer B. Shah, Ross M. Mandeville and Justin M. Brown
Cells 2024, 13(14), 1231; https://doi.org/10.3390/cells13141231 - 22 Jul 2024
Viewed by 1493
Abstract
Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within [...] Read more.
Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within a limited time window. The distal nerve deprived of axons also undergoes degeneration and fibrosis making it less receptive to axons. In this review, we describe the LMN injury associated with SCI and its clinical consequences. The process of degeneration of the muscle and nerve is broken down into the primary components of the neuromuscular circuit and reviewed, including the nerve and Schwann cells, the neuromuscular junction, and the muscle. Finally, we discuss three promising strategies to reverse denervation atrophy. These include providing surrogate axons from local sources; introducing stem cell-derived spinal motor neurons into the nerve to provide the missing axons; and finally, instituting a training program of high-energy electrical stimulation to directly rehabilitate these muscles. Successful interventions for denervation atrophy would significantly expand reconstructive options for cervical SCI and could be transformative for the predominantly LMN injuries of the conus medullaris and cauda equina. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
►▼ Show Figures

Figure 1

21 pages, 2415 KiB  
Article
A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders
by Randall D. Marshall, Frank S. Menniti and Mark A. Tepper
Cells 2024, 13(14), 1230; https://doi.org/10.3390/cells13141230 - 22 Jul 2024
Viewed by 1064
Abstract
Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and [...] Read more.
Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05–0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A’s inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders. Full article
(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)
►▼ Show Figures

Figure 1

17 pages, 17985 KiB  
Article
Achyranthis radix Extract Enhances Antioxidant Effect of Placenta-Derived Mesenchymal Stem Cell on Injured Human Ocular Cells
by Dae-Hyun Lee, Ji Woong Han, Hyeri Park, Se Jin Hong, Chan-Sik Kim, Young Sook Kim, Ik Soo Lee and Gi Jin Kim
Cells 2024, 13(14), 1229; https://doi.org/10.3390/cells13141229 - 21 Jul 2024
Viewed by 959
Abstract
Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to [...] Read more.
Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases. Full article
(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)
►▼ Show Figures

Figure 1

10 pages, 555 KiB  
Perspective
The Role of Glutamate and Blood–Brain Barrier Disruption as a Mechanistic Link between Epilepsy and Depression
by Benjamin F. Gruenbaum, Antonia Schonwald, Matthew Boyko and Alexander Zlotnik
Cells 2024, 13(14), 1228; https://doi.org/10.3390/cells13141228 - 21 Jul 2024
Viewed by 1282
Abstract
Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of the condition, significantly impacting quality of life. The goal of this review was to uncover how the pathological consequences of epilepsy, such as excessive glutamate release and a disrupted [...] Read more.
Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of the condition, significantly impacting quality of life. The goal of this review was to uncover how the pathological consequences of epilepsy, such as excessive glutamate release and a disrupted blood–brain barrier (BBB), contribute to the emergence of neuropsychiatric disorders. We hypothesize that epilepsy induces a dysfunctional BBB through hyperexcitation, which then further amplifies post-ictal glutamate levels and, thus, triggers neurodegenerative and neuropsychiatric processes. This review identifies the determinants of glutamate concentration levels in the brain and explores potential therapeutic interventions that restore BBB integrity. Our focus on therapeutic BBB restoration is guided by the premise that it may improve glutamate regulation, consequently mitigating the neurotoxicity that contributes to the onset of neuropsychiatric symptoms. Full article
(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Epilepsy)
►▼ Show Figures

Figure 1

14 pages, 15375 KiB  
Article
Fat Phagocytosis Promotes Anti-Inflammatory Responses of Macrophages in a Mouse Model of Osteonecrosis
by Zhuo Deng, Harry K. W. Kim, Paula A. Hernandez and Yinshi Ren
Cells 2024, 13(14), 1227; https://doi.org/10.3390/cells13141227 - 20 Jul 2024
Cited by 1 | Viewed by 1031
Abstract
Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of the blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the [...] Read more.
Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of the blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the inflammatory responses in ON. It is unclear what the dynamic phenotypes of macrophages are and what mechanisms may affect macrophage polarization and, therefore, the healing process. In our preliminary study, we found that there is an invasion of macrophages into the repair tissue during ON healing. Interestingly, in both ONFH patients and a mouse ON model, fat was co-labeled within macrophages using immunofluorescence staining, indicating the phagocytosis of fat by macrophages. To study the effects of fat phagocytosis on the macrophage phenotype, we set up an in vitro macrophage and fat co-culture system. We found that fat phagocytosis significantly decreased M1 marker expression, such as IL1β and iNOS, in macrophages, whereas the expression of the M2 marker Arg1 was significantly increased with fat phagocytosis. To investigate whether the polarization change is indeed mediated by phagocytosis, we treated the cells with Latrunculin A (LA, which inhibits actin polymerization and phagocytosis). LA supplementation significantly reversed the polarization marker gene changes induced by fat phagocytosis. To provide an unbiased transcriptional gene analysis, we submitted the RNA for bulk RNA sequencing. Differential gene expression (DGE) analysis revealed that the top upregulated genes were related to anti-inflammatory responses, while proinflammatory genes were significantly downregulated. Additionally, using pathway enrichment and network analyses (Metascape), we confirmed that gene-enriched categories related to proinflammatory responses were significantly downregulated in macrophages with fat phagocytosis. Finally, we validated the similar macrophage phenotype changes in vivo. To summarize, we discovered that fat phagocytosis occurs in both ONFH patients and an ON mouse model, which inhibits proinflammatory responses with increased anabolic gene expression in macrophages. This fat-phagocytosis-induced macrophage phenotype is consistent with the in vivo changes shown in the ON mouse model. Our study reveals a novel phagocytosis-mediated macrophage polarization mechanism in ON, which fills in our knowledge gaps of macrophage functions and provides new concepts in macrophage immunomodulation as a promising treatment for ON. Full article
(This article belongs to the Special Issue Signaling Regulation of Bone and Tooth Development)
►▼ Show Figures

Graphical abstract

27 pages, 12664 KiB  
Article
Genotype-Specific Activation of Autophagy during Heat Wave in Wheat
by Kathleen Hickey, Yunus Şahin, Glenn Turner, Taras Nazarov, Vadim Jitkov, Mike Pumphrey and Andrei Smertenko
Cells 2024, 13(14), 1226; https://doi.org/10.3390/cells13141226 - 20 Jul 2024
Viewed by 804
Abstract
Recycling of unnecessary or dysfunctional cellular structures through autophagy plays a critical role in cellular homeostasis and environmental resilience. Therefore, the autophagy trait may have been unintentionally selected in wheat breeding programs for higher yields in arid climates. This hypothesis was tested by [...] Read more.
Recycling of unnecessary or dysfunctional cellular structures through autophagy plays a critical role in cellular homeostasis and environmental resilience. Therefore, the autophagy trait may have been unintentionally selected in wheat breeding programs for higher yields in arid climates. This hypothesis was tested by measuring the response of three common autophagy markers, ATG7, ATG8, and NBR1, to a heat wave under reduced soil moisture content in 16 genetically diverse spring wheat landraces originating from different geographical locations. We observed in the greenhouse trials that ATG8 and NBR1 exhibited genotype-specific responses to a 1 h, 40 °C heat wave, while ATG7 did not show a consistent response. Three genotypes from Uruguay, Mozambique, and Afghanistan showed a pattern consistent with higher autophagic activity: decreased or stable abundance of both ATG8 and NBR1 proteins, coupled with increased transcription of ATG8 and NBR1. In contrast, three genotypes from Pakistan, Ethiopia, and Egypt exhibited elevated ATG8 protein levels alongside reduced or unaltered ATG8 transcript levels, indicating a potential suppression or no change in autophagic activity. Principal component analysis demonstrated a correlation between lower abundance of ATG8 and NBR1 proteins and higher yield in the field trials. We found that (i) the combination of heat and drought activated autophagy only in several genotypes, suggesting that despite being a resilience mechanism, autophagy is a heat-sensitive process; (ii) higher autophagic activity correlates positively with greater yield; (iii) the lack of autophagic activity in some high-yielding genotypes suggests contribution of alternative stress-resilient mechanisms; and (iv) enhanced autophagic activity in response to heat and drought was independently selected by wheat breeding programs in different geographic locations. Full article
(This article belongs to the Special Issue Role of Autophagy in Plant Cells)
►▼ Show Figures

Figure 1

19 pages, 3091 KiB  
Article
A Novel Pyrazole Exhibits Potent Anticancer Cytotoxicity via Apoptosis, Cell Cycle Arrest, and the Inhibition of Tubulin Polymerization in Triple-Negative Breast Cancer Cells
by Edgar A. Borrego, Cristina D. Guerena, Austre Y. Schiaffino Bustamante, Denisse A. Gutierrez, Carlos A. Valenzuela, Ana P. Betancourt, Armando Varela-Ramirez and Renato J. Aguilera
Cells 2024, 13(14), 1225; https://doi.org/10.3390/cells13141225 - 20 Jul 2024
Viewed by 1457
Abstract
In this study, we screened a chemical library to find potent anticancer compounds that are less cytotoxic to non-cancerous cells. This study revealed that pyrazole PTA-1 is a potent anticancer compound. Additionally, we sought to elucidate its mechanism of action (MOA) in triple-negative [...] Read more.
In this study, we screened a chemical library to find potent anticancer compounds that are less cytotoxic to non-cancerous cells. This study revealed that pyrazole PTA-1 is a potent anticancer compound. Additionally, we sought to elucidate its mechanism of action (MOA) in triple-negative breast cancer cells. Cytotoxicity was analyzed with the differential nuclear staining assay (DNS). Additional secondary assays were performed to determine the MOA of the compound. The potential MOA of PTA-1 was assessed using whole RNA sequencing, Connectivity Map (CMap) analysis, in silico docking, confocal microscopy, and biochemical assays. PTA-1 is cytotoxic at a low micromolar range in 17 human cancer cell lines, demonstrating less cytotoxicity to non-cancerous human cells, indicating a favorable selective cytotoxicity index (SCI) for the killing of cancer cells. PTA-1 induced phosphatidylserine externalization, caspase-3/7 activation, and DNA fragmentation in triple-negative breast MDA-MB-231 cells, indicating that it induces apoptosis. Additionally, PTA-1 arrests cells in the S and G2/M phases. Furthermore, gene expression analysis revealed that PTA-1 altered the expression of 730 genes at 24 h (198 upregulated and 532 downregulated). A comparison of these gene signatures with those within CMap indicated a profile similar to that of tubulin inhibitors. Subsequent studies revealed that PTA-1 disrupts microtubule organization and inhibits tubulin polymerization. Our results suggest that PTA-1 is a potent drug with cytotoxicity to various cancer cells, induces apoptosis and cell cycle arrest, and inhibits tubulin polymerization, indicating that PTA-1 is an attractive drug for future clinical cancer treatment. Full article
(This article belongs to the Topic Novel Discoveries in Oncology)
►▼ Show Figures

Figure 1

10 pages, 5330 KiB  
Communication
Developing Device of Death Operation (DODO) to Detect Apoptosis in 2D and 3D Cultures
by Ziheng Zhang, Zhe Sun and Ji-Long Liu
Cells 2024, 13(14), 1224; https://doi.org/10.3390/cells13141224 - 20 Jul 2024
Viewed by 705
Abstract
The real-time detection of intracellular biological processes by encoded sensors has broad application prospects. Here, we developed a degron-based modular reporting system, the Device of Death Operation (DODO), that can monitor various biological processes. The DODO system consists of a “reporter”, an “inductor”, [...] Read more.
The real-time detection of intracellular biological processes by encoded sensors has broad application prospects. Here, we developed a degron-based modular reporting system, the Device of Death Operation (DODO), that can monitor various biological processes. The DODO system consists of a “reporter”, an “inductor”, and a “degron”. After zymogen activation and cleavage, the degron will be released from the “reporter”, which eventually leads to the stabilization of the “reporter”, and can be detected. By replacing different “inductors” and “reporters”, a series of biological processes can be reported through various signals. The system can effectively report the existence of TEV protease. To prove this concept, we successfully applied the DODO system to report apoptosis in 2D and 3D cultures. In addition, the reporter based on degron will help to design protease reporters other than caspase. Full article
(This article belongs to the Section Cellular Pathology)
►▼ Show Figures

Figure 1

14 pages, 1454 KiB  
Review
Controlling the Expression Level of the Neuronal Reprogramming Factors for a Successful Reprogramming Outcome
by Natalie Mseis-Jackson, Mehek Sharma and Hedong Li
Cells 2024, 13(14), 1223; https://doi.org/10.3390/cells13141223 - 20 Jul 2024
Viewed by 1576
Abstract
Neuronal reprogramming is a promising approach for making major advancement in regenerative medicine. Distinct from the approach of induced pluripotent stem cells, neuronal reprogramming converts non-neuronal cells to neurons without going through a primitive stem cell stage. In vivo neuronal reprogramming brings this [...] Read more.
Neuronal reprogramming is a promising approach for making major advancement in regenerative medicine. Distinct from the approach of induced pluripotent stem cells, neuronal reprogramming converts non-neuronal cells to neurons without going through a primitive stem cell stage. In vivo neuronal reprogramming brings this approach to a higher level by changing the cell fate of glial cells to neurons in neural tissue through overexpressing reprogramming factors. Despite the ongoing debate over the validation and interpretation of newly generated neurons, in vivo neuronal reprogramming is still a feasible approach and has the potential to become clinical treatment with further optimization and refinement. Here, we discuss the major neuronal reprogramming factors (mostly pro-neurogenic transcription factors during development), especially the significance of their expression levels during neurogenesis and the reprogramming process focusing on NeuroD1. In the developing central nervous system, these pro-neurogenic transcription factors usually elicit distinct spatiotemporal expression patterns that are critical to their function in generating mature neurons. We argue that these dynamic expression patterns may be similarly needed in the process of reprogramming adult cells into neurons and further into mature neurons with subtype identities. We also summarize the existing approaches and propose new ones that control gene expression levels for a successful reprogramming outcome. Full article
►▼ Show Figures

Graphical abstract

26 pages, 4291 KiB  
Article
A Transcriptomics Analysis of the Regulation of Lens Fiber Cell Differentiation in the Absence of FGFRs and PTEN
by Anil Upreti, Stephanie L. Padula, Jacob M. Weaver, Brad D. Wagner, Allison M. Kneller, Anthony L. Petulla, Salil A. Lachke and Michael L. Robinson
Cells 2024, 13(14), 1222; https://doi.org/10.3390/cells13141222 - 19 Jul 2024
Viewed by 900
Abstract
Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the [...] Read more.
Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of β-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrate that many of the vitreous-induced gene-expression changes in Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten. Full article
(This article belongs to the Collection Fibroblast Growth Factors: Pathophysiology and Therapeutics)
►▼ Show Figures

Figure 1

39 pages, 21495 KiB  
Review
KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways
by Koushik Mondal, Mahesh Kumar Posa, Revathi P. Shenoy and Susanta Roychoudhury
Cells 2024, 13(14), 1221; https://doi.org/10.3390/cells13141221 - 19 Jul 2024
Cited by 2 | Viewed by 1849
Abstract
The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of [...] Read more.
The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
►▼ Show Figures

Graphical abstract

19 pages, 6090 KiB  
Article
1H and 31P Magnetic Resonance Spectroscopic Metabolomic Imaging: Assessing Mitogen-Activated Protein Kinase Inhibition in Melanoma
by Pradeep Kumar Gupta, Stepan Orlovskiy, Fernando Arias-Mendoza, David S. Nelson and Kavindra Nath
Cells 2024, 13(14), 1220; https://doi.org/10.3390/cells13141220 - 19 Jul 2024
Viewed by 841
Abstract
The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40–60% of melanomas. Inhibitors of this pathway’s BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, [...] Read more.
The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40–60% of melanomas. Inhibitors of this pathway’s BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma’s response to MEK inhibition. Full article
(This article belongs to the Collection Tumor Microenvironment: Interaction and Metabolism)
►▼ Show Figures

Figure 1

2 pages, 560 KiB  
Correction
Correction: Alves et al. WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line. Cells 2020, 9, 485
by Ana Laura Vieira Alves, Angela Margarida Costa, Olga Martinho, Vinicius Duval da Silva, Peter Jordan, Viviane Aline Oliveira Silva and Rui Manuel Reis
Cells 2024, 13(14), 1219; https://doi.org/10.3390/cells13141219 - 19 Jul 2024
Viewed by 539
Abstract
Error in Figure [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
►▼ Show Figures

Figure 2

23 pages, 3969 KiB  
Article
Enhanced Migration of Fuchs Corneal Endothelial Cells by Rho Kinase Inhibition: A Novel Ex Vivo Descemet’s Stripping Only Model
by Mohit Parekh, Annie Miall, Ashley Chou, Lara Buhl, Neha Deshpande, Marianne O. Price, Francis W. Price and Ula V. Jurkunas
Cells 2024, 13(14), 1218; https://doi.org/10.3390/cells13141218 - 19 Jul 2024
Viewed by 1344
Abstract
Descemet’s Stripping Only (DSO) is a surgical technique that utilizes the peripheral corneal endothelial cell (CEnC) migration for wound closure. Ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, has shown potential in DSO treatment; however, its mechanism in promoting CEnC migration remains unclear. We [...] Read more.
Descemet’s Stripping Only (DSO) is a surgical technique that utilizes the peripheral corneal endothelial cell (CEnC) migration for wound closure. Ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, has shown potential in DSO treatment; however, its mechanism in promoting CEnC migration remains unclear. We observed that ripasudil-treated immortalized normal and Fuchs endothelial corneal dystrophy (FECD) cells exhibited significantly enhanced migration and wound healing, particularly effective in FECD cells. Ripasudil upregulated mRNA expression of Snail Family Transcriptional Repressor (SNAI1/2) and Vimentin (VIM) while decreasing Cadherin (CDH1), indicating endothelial-to-mesenchymal transition (EMT) activation. Ripasudil activated Rac1, driving the actin-related protein complex (ARPC2) to the leading edge, facilitating enhanced migration. Ex vivo studies on cadaveric and FECD Descemet’s membrane (DM) showed increased migration and proliferation of CEnCs after ripasudil treatment. An ex vivo DSO model demonstrated enhanced migration from the DM to the stroma with ripasudil. Coating small incision lenticule extraction (SMILE) tissues with an FNC coating mix and treating the cells in conjunction with ripasudil further improved migration and resulted in a monolayer formation, as detected by the ZO-1 junctional marker, thereby leading to the reduction in EMT. In conclusion, ripasudil effectively enhanced cellular migration, particularly in a novel ex vivo DSO model, when the stromal microenvironment was modulated. This suggests ripasudil as a promising adjuvant for DSO treatment, highlighting its potential clinical significance. Full article
(This article belongs to the Special Issue Molecular Insights into Corneal Wound Healing and Inflammation)
►▼ Show Figures

Graphical abstract

18 pages, 6837 KiB  
Article
Widespread Distribution of Luteinizing Hormone/Choriogonadotropin Receptor in Human Juvenile Angiofibroma: Implications for a Sex-Specific Nasal Tumor
by Silke Wemmert, Martina Pyrski, Lukas Pillong, Maximilian Linxweiler, Frank Zufall, Trese Leinders-Zufall and Bernhard Schick
Cells 2024, 13(14), 1217; https://doi.org/10.3390/cells13141217 - 19 Jul 2024
Viewed by 833
Abstract
Juvenile angiofibroma (JA) is a rare, sex-specific, and highly vascularized nasal tumor that almost exclusively affects male adolescents, but its etiology has been controversial. The G protein-coupled hormone receptor LHCGR [luteinizing hormone (LH)/choriogonadotropin (hCG) receptor] represents a promising new candidate for elucidating the [...] Read more.
Juvenile angiofibroma (JA) is a rare, sex-specific, and highly vascularized nasal tumor that almost exclusively affects male adolescents, but its etiology has been controversial. The G protein-coupled hormone receptor LHCGR [luteinizing hormone (LH)/choriogonadotropin (hCG) receptor] represents a promising new candidate for elucidating the underlying mechanisms of sex specificity, pubertal manifestation, and JA progression. We used highly sensitive RNAscope technology, together with immunohistochemistry, to investigate the cellular expression, localization, and distribution of LHCGR in tissue samples from JA patients. Our results provide evidence for LHCGR expression in subsets of cells throughout JA tissue sections, with the majority of LHCGR+ cells located in close vicinity to blood vessels, rendering them susceptible to endocrine LH/hCG signaling, but LHCGR+ cells were also detected in fibrocollagenous stroma. A majority of LHCGR+ cells located near the vascular lumen co-expressed the neural crest stem cell marker CD271. These results are intriguing as both LH and hCG are produced in a time- and sex-dependent manner, and are known to be capable of inducing cell proliferation and angiogenesis. Our results give rise to a new model that suggests endocrine mechanisms involving LHCGR and its ligands, together with autocrine and paracrine signaling, in JA vascularization and cell proliferation. Full article
►▼ Show Figures

Figure 1

12 pages, 3282 KiB  
Article
Graft-Specific Regulatory T Cells for Long-Lasting, Local Tolerance Induction
by Nadja Seltrecht, Matthias Hardtke-Wolenski, Konstantinos Iordanidis, Danny Jonigk, Melanie Galla, Axel Schambach, Laura Elisa Buitrago-Molina, Heiner Wedemeyer, Fatih Noyan and Elmar Jaeckel
Cells 2024, 13(14), 1216; https://doi.org/10.3390/cells13141216 - 19 Jul 2024
Viewed by 968
Abstract
Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent [...] Read more.
Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models. Methods: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients. By utilizing an immunogenic skin transplant model and existing transplantation medicine reagents, we facilitated the clinical translation of our findings. Specifically, antigen-specific Tregs were used. Results: Our study demonstrated that combining the available induction therapies with drug-induced T-cell proliferation due to lymphopenia effectively increased the Treg/T effector ratios. This results in significant Treg accumulation within the graft, leading to long-term tolerance after the transfer of antigen-specific Tregs. Importantly, all the animals achieved operational tolerance, which boosted the presence of adoptively transferred Tregs within the graft. Conclusions: This protocol offers a means to establish tolerance by utilizing antigen-specific Tregs. These results have promising implications for future trials involving adoptive Treg therapy in organ transplantation. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
►▼ Show Figures

Figure 1

21 pages, 3924 KiB  
Review
Dissecting the Natural Patterns of Progression and Senescence in Pediatric Low-Grade Glioma: From Cellular Mechanisms to Clinical Implications
by David Gorodezki, Martin U. Schuhmann, Martin Ebinger and Jens Schittenhelm
Cells 2024, 13(14), 1215; https://doi.org/10.3390/cells13141215 - 19 Jul 2024
Viewed by 2809
Abstract
Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- [...] Read more.
Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach. Full article
(This article belongs to the Special Issue Pathophysiology of Central Nervous System Tumors)
►▼ Show Figures

Graphical abstract

34 pages, 2835 KiB  
Review
Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson’s Disease
by Woong Choi, Seongkwang Cha and Kyoungmi Kim
Cells 2024, 13(14), 1214; https://doi.org/10.3390/cells13141214 - 18 Jul 2024
Cited by 1 | Viewed by 1656
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In [...] Read more.
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson’s disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
►▼ Show Figures

Graphical abstract

15 pages, 1077 KiB  
Article
Differentiating Stages of Bipolar and Unipolar Depression—The Possible Role of sICAM-1 and sVCAM-1
by Maja Pantovic-Stefanovic, Natasa Petronijevic, Bojana Dunjic-Kostic, Milica Velimirovic, Vladimir Jurisic, Tatjana Nikolic, Sara Dodic and Maja Ivkovic
Cells 2024, 13(14), 1213; https://doi.org/10.3390/cells13141213 - 18 Jul 2024
Viewed by 788
Abstract
Increased immune–inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation [...] Read more.
Increased immune–inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders. Full article
(This article belongs to the Section Cellular Immunology)
►▼ Show Figures

Figure 1

14 pages, 1034 KiB  
Article
Identification of Genomic Predictors of Muscle Fiber Size
by João Paulo L. F. Guilherme, Ekaterina A. Semenova, Naoki Kikuchi, Hiroki Homma, Ayumu Kozuma, Mika Saito, Hirofumi Zempo, Shingo Matsumoto, Naoyuki Kobatake, Koichi Nakazato, Takanobu Okamoto, George John, Rinat A. Yusupov, Andrey K. Larin, Nikolay A. Kulemin, Ilnaz M. Gazizov, Edward V. Generozov and Ildus I. Ahmetov
Cells 2024, 13(14), 1212; https://doi.org/10.3390/cells13141212 - 18 Jul 2024
Viewed by 1643
Abstract
The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the [...] Read more.
The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed–strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Exercise and Healthspan 2.0)
►▼ Show Figures

Figure 1

21 pages, 6235 KiB  
Article
Tissue-Level Integration Overrides Gradations of Differentiating Cell Identity in Beetle Extraembryonic Tissue
by Katie E. Mann and Kristen A. Panfilio
Cells 2024, 13(14), 1211; https://doi.org/10.3390/cells13141211 - 18 Jul 2024
Viewed by 694
Abstract
During animal embryogenesis, one of the earliest specification events distinguishes extraembryonic (EE) from embryonic tissue fates: the serosa in the case of the insects. While it is well established that the homeodomain transcription factor Zen1 is the critical determinant of the serosa, the [...] Read more.
During animal embryogenesis, one of the earliest specification events distinguishes extraembryonic (EE) from embryonic tissue fates: the serosa in the case of the insects. While it is well established that the homeodomain transcription factor Zen1 is the critical determinant of the serosa, the subsequent realization of this tissue’s identity has not been investigated. Here, we examine serosal differentiation in the beetle Tribolium castaneum based on the quantification of morphological and morphogenetic features, comparing embryos from a Tc-zen1 RNAi dilution series, where complete knockdown results in amnion-only EE tissue identity. We assess features including cell density, tissue boundary morphology, and nuclear size as dynamic readouts for progressive tissue maturation. While some features exhibit an all-or-nothing outcome, other key features show dose-dependent phenotypic responses with trait-specific thresholds. Collectively, these findings provide nuance beyond the known status of Tc-Zen1 as a selector gene for serosal tissue patterning. Overall, our approach illustrates how the analysis of tissue maturation dynamics from live imaging extends but also challenges interpretations based on gene expression data, refining our understanding of tissue identity and when it is achieved. Full article
(This article belongs to the Special Issue Patterns across Developmental Scales)
►▼ Show Figures

Figure 1

19 pages, 8723 KiB  
Article
Intake of Special Amino Acids Mixture Leads to Blunted Murine Colon Cancer Growth In Vitro and In Vivo
by Giovanni Corsetti, Claudia Romano, Silvia Codenotti, Lorena Giugno, Evasio Pasini, Alessandro Fanzani, Tiziano Scarabelli and Francesco S. Dioguardi
Cells 2024, 13(14), 1210; https://doi.org/10.3390/cells13141210 - 18 Jul 2024
Viewed by 838
Abstract
Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell [...] Read more.
Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix and in mice fed with EAA-rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable antiproliferative properties. Full article
►▼ Show Figures

Graphical abstract

37 pages, 5984 KiB  
Review
Targeting DNA Methylation Machinery in Pediatric Solid Tumors
by Camilla Cristalli and Katia Scotlandi
Cells 2024, 13(14), 1209; https://doi.org/10.3390/cells13141209 - 18 Jul 2024
Viewed by 1558
Abstract
DNA methylation is a key epigenetic regulatory mechanism that plays a critical role in a variety of cellular processes, including the regulation of cell fate during development, maintenance of cell identity, and genome stability. DNA methylation is tightly regulated by enzymatic reactions and [...] Read more.
DNA methylation is a key epigenetic regulatory mechanism that plays a critical role in a variety of cellular processes, including the regulation of cell fate during development, maintenance of cell identity, and genome stability. DNA methylation is tightly regulated by enzymatic reactions and its deregulation plays an important role in the development of cancer. Specific DNA methylation alterations have been found in pediatric solid tumors, providing new insights into the development of these tumors. In addition, DNA methylation profiles have greatly contributed to tune the diagnosis of pediatric solid tumors and to define subgroups of patients with different risks of progression, leading to the reduction in unwanted toxicity and the improvement of treatment efficacy. This review highlights the dysregulated DNA methylome in pediatric solid tumors and how this information provides promising targets for epigenetic therapies, particularly inhibitors of DNMT enzymes (DNMTis). Opportunities and limitations are considered, including the ability of DNMTis to induce viral mimicry and immune signaling by tumors. Besides intrinsic action against cancer cells, DNMTis have the potential to sensitize immune-cold tumors to immunotherapies and may represent a remarkable option to improve the treatment of challenging pediatric solid tumors. Full article
►▼ Show Figures

Figure 1

20 pages, 6164 KiB  
Article
HSV-1 and Cellular miRNAs in CSF-Derived Exosomes as Diagnostically Relevant Biomarkers for Neuroinflammation
by Christian Scheiber, Hans C. Klein, Julian M. Schneider, Tanja Schulz, Karl Bechter, Hayrettin Tumani, Thomas Kapapa, Dani Flinkman, Eleanor Coffey, Duncan Ross, Maksims Čistjakovs, Zaiga Nora-Krūkle, Daria Bortolotti, Roberta Rizzo, Modra Murovska and E. Marion Schneider
Cells 2024, 13(14), 1208; https://doi.org/10.3390/cells13141208 - 17 Jul 2024
Cited by 1 | Viewed by 3568
Abstract
Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant [...] Read more.
Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant mediators of cellular communication. The current study questioned the role of HSV-1-encoded and host-derived miRNAs in cerebrospinal fluid (CSF)-derived exosomes, enriched from stress-induced neuroinflammatory diseases, mainly subarachnoid hemorrhage (SAH), psychiatric disorders (AF and SZ), and various other neuroinflammatory diseases. The results were compared with CSF exosomes from control donors devoid of any neuroinflammatory pathology. Serology proved positive, but variable immunity against herpesviruses in the majority of patients, except controls. Selective ultrastructural examinations identified distinct, herpesvirus-like particles in CSF-derived lymphocytes and monocytes. The likely release of extracellular vesicles and exosomes was most frequently observed from CSF monocytes. The exosomes released were structurally similar to highly purified stem-cell-derived exosomes. Exosomal RNA was quantified for HSV-1-derived miR-H2-3p, miR-H3-3p, miR-H4-3p, miR-H4-5p, miR-H6-3p, miR-H27 and host-derived miR-21-5p, miR-146a-5p, miR-155-5p, and miR-138-5p and correlated with the oxidative stress chemokine IL-8 and the axonal damage marker neurofilament light chain (NfL). Replication-associated miR-H27 correlated with neuronal damage marker NfL, and cell-derived miR-155-5p correlated with oxidative stress marker IL-8. Elevated miR-138-5p targeting HSV-1 latency-associated ICP0 inversely correlated with lower HSV-1 antibodies in CSF. In summary, miR-H27 and miR-155-5p may constitute neuroinflammatory markers for delineating frequent and fluctuating HSV-1 replication and NfL-related axonal damage in addition to the oxidative stress cytokine IL-8 in the brain. Tentatively, HSV-1 remains a relevant pathogen conditioning autoimmune processes and a psychiatric clinical phenotype. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Autoimmune Encephalitis: Biology and Potential Therapeutic Implications)
►▼ Show Figures

Graphical abstract

15 pages, 5244 KiB  
Communication
APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons
by Vanessa Budny, Yannic Knöpfli, Debora Meier, Kathrin Zürcher, Chantal Bodenmann, Siri L. Peter, Terry Müller, Marie Tardy, Cedric Cortijo and Christian Tackenberg
Cells 2024, 13(14), 1207; https://doi.org/10.3390/cells13141207 - 17 Jul 2024
Cited by 1 | Viewed by 1276
Abstract
The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis [...] Read more.
The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism. Full article
(This article belongs to the Special Issue Mitochondria and Other Organelles in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

19 pages, 1150 KiB  
Review
Markers of Dermal Fibroblast Subpopulations for Viable Cell Isolation via Cell Sorting: A Comprehensive Review
by Krzysztof Łuszczyński, Marta Soszyńska, Michał Komorowski, Paulina Lewandowska, Robert Zdanowski, Anna Sobiepanek, Marek Brytan, Jacek Malejczyk, Anna Lutyńska and Aneta Ścieżyńska
Cells 2024, 13(14), 1206; https://doi.org/10.3390/cells13141206 - 17 Jul 2024
Cited by 1 | Viewed by 1583
Abstract
Fibroblasts are among the most abundant cell types in the human body, playing crucial roles in numerous physiological processes, including the structural maintenance of the dermis, production of extracellular matrix components, and mediation of inflammatory responses. Despite their importance, fibroblasts remain one of [...] Read more.
Fibroblasts are among the most abundant cell types in the human body, playing crucial roles in numerous physiological processes, including the structural maintenance of the dermis, production of extracellular matrix components, and mediation of inflammatory responses. Despite their importance, fibroblasts remain one of the least characterized cell populations. The advent of single-cell analysis techniques, particularly single-cell RNA sequencing (scRNA-seq) and fluorescence-activated cell sorting (FACS), has enabled detailed investigations into fibroblast biology. In this study, we present an extensive analysis of fibroblast surface markers suitable for cell sorting and subsequent functional studies. We reviewed over three thousand research articles describing fibroblast populations and their markers, characterizing and comparing subtypes based on their surface markers, as well as their intra- and extracellular proteins. Our detailed analysis identified a variety of distinct fibroblast subpopulations, each with unique markers, characteristics dependent on their location, and the physiological or pathophysiological environment. These findings underscore the diversity of fibroblasts as a cellular population and could lead to the development of novel diagnostic and therapeutic tools. Full article
►▼ Show Figures

Figure 1

7 pages, 945 KiB  
Brief Report
The Novel Cytokine Interleukin-41/Meteorin-like Is Reduced in Diffuse Systemic Sclerosis
by Paul Freedman, Bettina Schock and Steven O’Reilly
Cells 2024, 13(14), 1205; https://doi.org/10.3390/cells13141205 - 17 Jul 2024
Viewed by 809
Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified [...] Read more.
Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts. Full article
(This article belongs to the Special Issue Fibrosis in Chronic Inflammatory Diseases)
►▼ Show Figures

Figure 1

17 pages, 4592 KiB  
Article
Single-Nucleotide Polymorphisms of TAS2R46 Affect the Receptor Downstream Calcium Regulation in Histamine-Challenged Cells
by Giulia Lecchi, Chiara Mocchetti, Davide Tunesi, Arianna Berto, Hari Baskar Balasubramanian, Sima Biswas, Angshuman Bagchi, Federica Pollastro, Luigia Grazia Fresu and Maria Talmon
Cells 2024, 13(14), 1204; https://doi.org/10.3390/cells13141204 - 16 Jul 2024
Viewed by 1082
Abstract
Bitter taste receptors (TAS2Rs) expressed in extraoral tissues represent a whole-body sensory system, whose role and mechanisms could be of interest for the identification of new therapeutic targets. It is known that TAS2R46s in pre-contracted airway smooth muscle cells increase mitochondrial calcium uptake, [...] Read more.
Bitter taste receptors (TAS2Rs) expressed in extraoral tissues represent a whole-body sensory system, whose role and mechanisms could be of interest for the identification of new therapeutic targets. It is known that TAS2R46s in pre-contracted airway smooth muscle cells increase mitochondrial calcium uptake, leading to bronchodilation, and that several SNPs have been identified in its gene sequence. There are very few reports on the structure–function analysis of TAS2Rs. Thus, we delved into the subject by using mutagenesis and in silico studies. We generated a cellular model that expresses native TAS2R46 to evaluate the influence of the four most common SNPs on calcium fluxes following the activation of the receptor by its specific ligand absinthin. Then, docking studies were conducted to correlate the calcium flux results to the structural mutation. The analysed SNPs differently modulate the TAS2R46 signal cascade according to the altered protein domain. In particular, the SNP in the sixth transmembrane domain of the receptors did not modulate calcium homeostasis, while the SNPs in the sequence coding for the fourth transmembrane domain completely abolished the mitochondrial calcium uptake. In conclusion, these results indicate the fourth transmembrane domain of TAS2R46 is critical for the intrinsic receptor activity. Full article
►▼ Show Figures

Graphical abstract

17 pages, 2027 KiB  
Review
Genetic Deficiencies of Hyaluronan Degradation
by Stephen P. Fink and Barbara Triggs-Raine
Cells 2024, 13(14), 1203; https://doi.org/10.3390/cells13141203 - 16 Jul 2024
Cited by 2 | Viewed by 948
Abstract
Hyaluronan (HA) is a large polysaccharide that is broadly distributed and highly abundant in the soft connective tissues and embryos of vertebrates. The constitutive turnover of HA is very high, estimated at 5 g per day in an average (70 kg) adult human, [...] Read more.
Hyaluronan (HA) is a large polysaccharide that is broadly distributed and highly abundant in the soft connective tissues and embryos of vertebrates. The constitutive turnover of HA is very high, estimated at 5 g per day in an average (70 kg) adult human, but HA turnover must also be tightly regulated in some processes. Six genes encoding homologues to bee venom hyaluronidase (HYAL1, HYAL2, HYAL3, HYAL4, HYAL6P/HYALP1, SPAM1/PH20), as well as genes encoding two unrelated G8-domain-containing proteins demonstrated to be involved in HA degradation (CEMIP/KIAA1199, CEMIP2/TMEM2), have been identified in humans. Of these, only deficiencies in HYAL1, HYAL2, HYAL3 and CEMIP have been identified as the cause or putative cause of human genetic disorders. The phenotypes of these disorders have been vital in determining the biological roles of these enzymes but there is much that is still not understood. Deficiencies in these HA-degrading proteins have been created in mice and/or other model organisms where phenotypes could be analyzed and probed to expand our understanding of HA degradation and function. This review will describe what has been found in human and animal models of hyaluronidase deficiency and discuss how this has advanced our understanding of HA’s role in health and disease. Full article
(This article belongs to the Special Issue Role of Hyaluronan in Human Health and Disease)
►▼ Show Figures

Figure 1

16 pages, 4678 KiB  
Article
RNA Binding Properties of SOX Family Members
by Seyed Mohammad Ghafoori, Ashish Sethi, Gayle F. Petersen, Mohammad Hossein Tanipour, Paul R. Gooley and Jade K. Forwood
Cells 2024, 13(14), 1202; https://doi.org/10.3390/cells13141202 - 16 Jul 2024
Viewed by 1077
Abstract
SOX proteins are a family of transcription factors (TFs) that play critical functions in sex determination, neurogenesis, and chondrocyte differentiation, as well as cardiac, vascular, and lymphatic development. There are 20 SOX family members in humans, each sharing a 79-residue L-shaped high mobility [...] Read more.
SOX proteins are a family of transcription factors (TFs) that play critical functions in sex determination, neurogenesis, and chondrocyte differentiation, as well as cardiac, vascular, and lymphatic development. There are 20 SOX family members in humans, each sharing a 79-residue L-shaped high mobility group (HMG)-box domain that is responsible for DNA binding. SOX2 was recently shown to interact with long non-coding RNA and large-intergenic non-coding RNA to regulate embryonic stem cell and neuronal differentiation. The RNA binding region was shown to reside within the HMG-box domain; however, the structural details of this binding remain unclear. Here, we show that all SOX family members, except group H, interact with RNA. Our mutational experiments demonstrate that the disordered C-terminal region of the HMG-box domain plays an important role in RNA binding. Further, by determining a high-resolution structure of the HMG-box domain of the group H family member SOX30, we show that despite differences in RNA binding ability, SOX30 shares a very similar secondary structure with other SOX protein HMG-box domains. Together, our study provides insight into the interaction of SOX TFs with RNA. Full article
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-66
Previous Issue
Next Issue
Back to TopTop