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Showing 1 - 200 of 246 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 4)
Actuators     Open Access   (Followers: 3)
Administrative Sciences     Open Access   (Followers: 4)
Aerospace     Open Access   (Followers: 70, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 7, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 13, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 14, SJR: 0.217, CiteScore: 1)
Allergies     Open Access   (Followers: 1)
Animals     Open Access   (Followers: 13, SJR: 0.744, CiteScore: 2)
Antibiotics     Open Access   (Followers: 11, SJR: 1.063, CiteScore: 3)
Antibodies     Open Access   (Followers: 2, SJR: 0.931, CiteScore: 3)
Antioxidants     Open Access   (Followers: 4, SJR: 0.847, CiteScore: 3)
Applied Sciences     Open Access   (Followers: 3, SJR: 0.303, CiteScore: 2)
Applied System Innovation     Open Access   (Followers: 1)
Arts     Open Access   (Followers: 3)
Atmosphere     Open Access   (Followers: 33)
Atoms     Open Access   (Followers: 1)
Audiology Research     Open Access   (Followers: 10)
Axioms     Open Access   (Followers: 1)
Batteries     Open Access   (Followers: 9)
Behavioral Sciences     Open Access   (Followers: 3)
Beverages     Open Access  
Big Data and Cognitive Computing     Open Access   (Followers: 6)
Bioengineering     Open Access   (Followers: 3)
Biology     Open Access   (Followers: 3, SJR: 1.324, CiteScore: 3)
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Biomolecules     Open Access   (Followers: 1, SJR: 2.552, CiteScore: 6)
Biosensors     Open Access   (Followers: 3, SJR: 0.829, CiteScore: 4)
Brain Sciences     Open Access   (Followers: 6, SJR: 1.047, CiteScore: 3)
Buildings     Open Access   (Followers: 7)
C - J. of Carbon Research     Open Access   (Followers: 5)
Cancers     Open Access   (Followers: 2, SJR: 2.243, CiteScore: 6)
Catalysts     Open Access   (Followers: 12)
Cells     Open Access   (Followers: 2, SJR: 2.742, CiteScore: 6)
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Challenges     Open Access   (Followers: 2)
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Clinics and Practice     Open Access   (SJR: 0.175, CiteScore: 1)
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Colloids and Interfaces     Open Access  
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Condensed Matter     Open Access   (Followers: 2)
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Cosmetics     Open Access   (Followers: 4)
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Crystals     Open Access   (Followers: 1, SJR: 0.566, CiteScore: 2)
Current Issues in Molecular Biology     Open Access   (Followers: 3, SJR: 0.787, CiteScore: 2)
Dairy     Open Access   (Followers: 2)
Data     Open Access   (Followers: 4)
Dentistry J.     Open Access   (Followers: 6)
Designs     Open Access  
Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
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Entropy     Open Access   (Followers: 5, SJR: 0.592, CiteScore: 2)
Environments     Open Access  
Epigenomes     Open Access  
European Burn J.     Open Access   (Followers: 11)
European J. of Investigation in Health, Psychology and Education     Open Access   (Followers: 5)
Fermentation     Open Access   (Followers: 2)
Fibers     Open Access   (Followers: 4)
Fire     Open Access   (Followers: 2)
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Forecasting     Open Access   (Followers: 1)
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Fractal and Fractional     Open Access  
Future Internet     Open Access   (Followers: 83, SJR: 0.219, CiteScore: 1)
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Infectious Disease Reports     Open Access   (Followers: 2, SJR: 0.66, CiteScore: 1)
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Information     Open Access   (Followers: 30, SJR: 0.222, CiteScore: 1)
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Inorganics     Open Access   (Followers: 1)
Insects     Open Access   (Followers: 1, SJR: 0.897, CiteScore: 2)
Instruments     Open Access  
Intl. J. of Environmental Research and Public Health     Open Access   (Followers: 25, SJR: 0.735, CiteScore: 2)
Intl. J. of Financial Studies     Open Access   (Followers: 4)
Intl. J. of Molecular Sciences     Open Access   (Followers: 2, SJR: 1.26, CiteScore: 4)
Intl. J. of Neonatal Screening     Open Access   (Followers: 3)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 20)
Inventions     Open Access  
IoT     Open Access   (Followers: 1)
ISPRS Intl. J. of Geo-Information     Open Access   (Followers: 6, SJR: 0.493, CiteScore: 2)
J : Multidisciplinary Scientific J.     Open Access  
J. of Cardiovascular Development and Disease     Open Access   (Followers: 1)
J. of Clinical Medicine     Open Access   (Followers: 3)
J. of Composites Science     Open Access   (Followers: 3)
J. of Cybersecurity and Privacy     Open Access   (Followers: 2)
J. of Developmental Biology     Open Access   (Followers: 3)
J. of Functional Biomaterials     Open Access   (Followers: 2, SJR: 0.685, CiteScore: 3)
J. of Functional Morphology and Kinesiology     Open Access  
J. of Fungi     Open Access   (Followers: 2)
J. of Imaging     Open Access   (Followers: 3)
J. of Intelligence     Open Access   (Followers: 3)
J. of Low Power Electronics and Applications     Open Access   (Followers: 8, SJR: 0.222, CiteScore: 1)
J. of Manufacturing and Materials Processing     Open Access  
J. of Marine Science and Engineering     Open Access   (Followers: 4)
J. of Nanotheranostics     Open Access  
J. of Open Innovation : Technology, Market, and Complexity     Open Access   (Followers: 1)
J. of Otorhinolaryngology, Hearing and Balance Medicine     Open Access   (Followers: 2)
J. of Personalized Medicine     Open Access   (Followers: 3, SJR: 1.269, CiteScore: 3)
J. of Risk and Financial Management     Open Access   (Followers: 10)
J. of Sensor and Actuator Networks     Open Access   (Followers: 10)
J. of Xenobiotics     Open Access  
J. of Zoological and Botanical Gardens     Open Access  
Land     Open Access   (Followers: 3)
Languages     Open Access   (Followers: 3)
Laws     Open Access   (Followers: 2)
Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
Literature     Open Access   (Followers: 1)
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Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 15)
Machines     Open Access   (Followers: 4)
Magnetochemistry     Open Access  
Marine Drugs     Open Access   (Followers: 1, SJR: 0.978, CiteScore: 5)
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Mathematical and Computational Applications     Open Access   (Followers: 3)
Mathematics     Open Access   (Followers: 3)
Medical Sciences     Open Access   (Followers: 1)
Medicines     Open Access   (Followers: 1)
Membranes     Open Access   (Followers: 3, SJR: 0.645, CiteScore: 3)
Metabolites     Open Access   (Followers: 2, SJR: 1.026, CiteScore: 3)
Metals     Open Access   (Followers: 4, SJR: 0.55, CiteScore: 2)
Methods and Protocols     Open Access  
Microarrays     Open Access  
Microbiology Research     Open Access   (Followers: 7)
Micromachines     Open Access   (Followers: 2, SJR: 0.493, CiteScore: 2)
Microorganisms     Open Access   (Followers: 5)
Minerals     Open Access   (SJR: 0.462, CiteScore: 2)
Molbank     Open Access   (Followers: 1, SJR: 0.12, CiteScore: 0)
Molecules     Open Access   (Followers: 4, SJR: 0.855, CiteScore: 3)
Multimodal Technologies and Interaction     Open Access  
Nanomaterials     Open Access   (Followers: 4)
Neuroglia     Open Access   (Followers: 1)
Neurology Intl.     Open Access   (Followers: 2, SJR: 0.345, CiteScore: 1)
Nitrogen     Open Access  
Non-Coding RNA     Open Access  
Nursing Reports     Open Access   (Followers: 2)
Nutrients     Open Access   (Followers: 13, SJR: 1.557, CiteScore: 4)
Oceans     Open Access  
Particles     Open Access  
Pathogens     Open Access   (Followers: 3, SJR: 1.421, CiteScore: 4)
Pathophysiology     Full-text available via subscription   (Followers: 1, SJR: 0.67, CiteScore: 2)
Pediatric Reports     Open Access   (SJR: 0.165, CiteScore: 1)
Pharmaceuticals     Open Access   (Followers: 4, SJR: 1.293, CiteScore: 4)
Pharmaceutics     Open Access   (Followers: 5, SJR: 0.949, CiteScore: 4)
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Photonics     Open Access   (Followers: 4, SJR: 0.709, CiteScore: 2)
Physics     Open Access   (Followers: 1)
Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 3)
Polymers     Open Access   (Followers: 20, SJR: 0.852, CiteScore: 3)
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Projects     Open Access   (Followers: 1)
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Proteomes     Open Access   (Followers: 1)
Psych     Open Access   (Followers: 1)
Publications     Open Access   (Followers: 7)
Quantum Beam Science     Open Access   (Followers: 1)

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Journal Prestige (SJR): 2.742
Citation Impact (citeScore): 6
Number of Followers: 2  

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ISSN (Online) 2073-4409
Published by MDPI Homepage  [246 journals]
  • Cells, Vol. 11, Pages 3835: cAMP-Dependent Signaling and Ovarian Cancer

    • Authors: Agnieszka Kilanowska, Agnieszka Ziółkowska, Piotr Stasiak, Magdalena Gibas-Dorna
      First page: 3835
      Abstract: cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA and EPAC—it regulates gene expression and many cellular functions. PKA promotes the phosphorylation of cAMP response element-binding protein (CREB) which mediates gene transcription, cell migration, mitochondrial homeostasis, cell proliferation, and death. EPAC, on the other hand, is involved in cell adhesion, binding, differentiation, and interaction between cell junctions. Ovarian cancer growth and metabolism largely depend on changes in the signal processing of the cAMP-PKA-CREB axis, often associated with neoplastic transformation, metastasis, proliferation, and inhibition of apoptosis. In addition, the intracellular level of cAMP also determines the course of other pathways including AKT, ERK, MAPK, and mTOR, that are hypo- or hyperactivated among patients with ovarian neoplasm. With this review, we summarize the current findings on cAMP signaling in the ovary and its association with carcinogenesis, multiplication, metastasis, and survival of cancer cells. Additionally, we indicate that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer.
      Citation: Cells
      PubDate: 2022-11-29
      DOI: 10.3390/cells11233835
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3836: Hypoxia-Induced HIF-1α Expression
           Promotes Neurogenic Bladder Fibrosis via EMT and Pyroptosis

    • Authors: Qi Li, Yifan Hong, Jing Chen, Xiazhu Zhou, Xiaomao Tian, Yihang Yu, Lianju Shen, Chunlan Long, Miao Cai, Shengde Wu, Guanghui Wei
      First page: 3836
      Abstract: Background: Neurogenic bladder (NB) patients exhibit varying degrees of bladder fibrosis, and the thickening and hardening of the bladder wall induced by fibrosis will further affect bladder function and cause renal failure. Our study aimed to investigate the mechanism of bladder fibrosis caused by a spinal cord injury (SCI). Methods: NB rat models were created by cutting the bilateral lumbar 6 (L6) and sacral 1 (S1) spinal nerves. RNA-seq, Western blotting, immunofluorescence, cell viability and ELISA were performed to assess the inflammation and fibrosis levels. Results: The rats showed bladder dysfunction, upper urinary tract damage and bladder fibrosis after SCI. RNA-seq results indicated that hypoxia, EMT and pyroptosis might be involved in bladder fibrosis induced by SCI. Subsequent Western blot, ELISA and cell viability assays and immunofluorescence of bladder tissue confirmed the RNA-seq findings. Hypoxic exposure increased the expression of HIF-1α and induced EMT and pyroptosis in bladder epithelial cells. Furthermore, HIF-1α knockdown rescued hypoxia-induced pyroptosis, EMT and fibrosis. Conclusion: EMT and pyroptosis were involved in the development of SCI-induced bladder fibrosis via the HIF-1α pathway. Inhibition of the HIF-1α pathway may serve as a potential target to alleviate bladder fibrosis caused by SCI.
      Citation: Cells
      PubDate: 2022-11-29
      DOI: 10.3390/cells11233836
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3837: Discovery of 16-Androstenes (Androstenone and
           Androstenol), Their Synthesis Pathway, and Possible Role in Reproduction
           of Mouse Deer (Moschiola indica)

    • Authors: Vinod Kumar, Shivakumara Manu, Karunakaran Caroline, Anupama Sekhar, Sajwan-Khatri Mamta, Mushkam Sandeep, Wasimuddin, Balasubramanian Senthilkumaran, Govindhaswamy Umapathy
      First page: 3837
      Abstract: We discovered odorous 16-androstenes (Androstenone and Androstenol) in endangered mouse deer during a captive breeding program. This study examined the molecular characteristics, their synthesis pathway, and the possible functional role of these compounds in the reproduction of mouse deer. CYP17A1 and CYB5 genes were cloned and expressed in HEK-293, COS-7 cell lines, and gonads of mouse deer to investigate the CYP17A1 gene’s andien-β-synthase activity towards the synthesis of 16-androstenes in mouse deer. An enzyme immunoassay was further developed and standardized to measure fecal androstenone during the reproductive cycles of mouse deer. Results showed that the mouse deer CYP17A1 gene possesses andien-β-synthase activity and could transform pregnenolone into 5,16-androstadien-3β-ol. The expression of the CYP17A1 gene upregulated in the testis and ovary compared to other tissues in mouse deer. Significantly elevated androstenone and estrogens were recorded prior to delivery and postpartum estrus/mating in mouse deer. Further, there were weak correlations between fecal androstenone and estrogens/androgens in mouse deer during the breeding season. These findings suggest that androstenone probably plays a role in the reproductive activities of mouse deer. This knowledge can be used for captive breeding programs of mouse deer in India and elsewhere.
      Citation: Cells
      PubDate: 2022-11-29
      DOI: 10.3390/cells11233837
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3838: Correction: Zheng et al. Geniposide
           Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts
           by Mediating the GLP-1R/ABCA1 Axis. Cells 2021, 10, 3424

    • Authors: Yizhou Zheng, Yaosheng Xiao, Di Zhang, Shanshan Zhang, Jing Ouyang, Linfu Li, Weimei Shi, Rui Zhang, Hai Liu, Qi Jin, Zhixi Chen, Daohua Xu, Longhuo Wu
      First page: 3838
      Abstract: The authors wish to make the following changes to their paper [...]
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233838
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3839: CAR Triggered Release of Type-1 Interferon
           Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

    • Authors: Dennis Christoph Harrer, Charlotte Schenkel, Valerie Bezler, Marcell Kaljanac, Jordan Hartley, Markus Barden, Hong Pan, Astrid Holzinger, Wolfgang Herr, Hinrich Abken
      First page: 3839
      Abstract: The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as “fourth generation” CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under “stress” conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233839
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3840: Do Tumor Mechanical Stresses Promote Cancer
           Immune Escape'

    • Authors: Killian Onwudiwe, Julian Najera, Saeed Siri, Meenal Datta
      First page: 3840
      Abstract: Immune evasion—a well-established cancer hallmark—is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities (notably, increased fluid and solid pressures applied both inside and outside the TME) that drive cancer mechanopathologies. Strikingly, in response to these mechanical stresses, cancer cells upregulate canonical immune evasion mechanisms, including epithelial–mesenchymal transition (EMT) and autophagy. Consideration and characterization of the origins and consequences of tumor mechanical stresses in the TME may yield novel strategies to combat immunotherapy resistance. In this Perspective, we posit that tumor mechanical stresses—namely fluid shear and solid stresses—induce immune evasion by upregulating EMT and autophagy. In addition to exploring the basis for our hypothesis, we also identify explicit gaps in the field that need to be addressed in order to directly demonstrate the existence and importance of this biophysical relationship. Finally, we propose that reducing or neutralizing fluid shear stress and solid stress-induced cancer immune escape may improve immunotherapy outcomes.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233840
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3841: Identification and Validation of RELN Mutation
           as a Response Indicator for Immune Checkpoint Inhibitor Therapy in
           Melanoma and Non-Small Cell Lung Cancer

    • Authors: Zhenpeng Li, Xin Wang, Yi Yang, Fuyan Shi, Wenjing Zhang, Qinghua Wang, Suzhen Wang
      First page: 3841
      Abstract: Remarkable clinical benefits in several advanced cancers are observed under the treatment of immune checkpoint inhibitor (ICI) agents. However, only a smaller proportion of patients respond to the treatments. Reelin (RELN) is frequently mutated in the cancer genome. In this study, the RELN mutation association with ICI treatment efficacy in melanoma and non-small cell lung cancer (NSCLC) was elucidated. Data from 631 melanoma and 109 NSCLC patients with both ICI treatment data and pre-treatment mutational profiles were collected. In addition, from the Cancer Genome Atlas (TCGA) project, we also obtained both tumors to explore the immunologic features behind RELN mutations. Melanoma patients with RELN mutations exhibited a favorable ICI survival benefit when compared with wild-type patients (HR: 0.66, 95% CI: 0.51–0.87, p = 0.003). A higher response rate was also noticed in RELN-mutated patients (38.9% vs. 28.3%, p = 0.017). The association of RELN mutations with a preferable immunotherapy outcome and response was further confirmed in NSCLC. Further exploration demonstrated that favorable immunocyte infiltration and immune response signaling pathways were found in patients with RELN mutations. In this study, RELN mutations were identified to connect with a better immune microenvironment and an improved ICI efficacy in melanoma and NSCLC, which provides a potential biomarker for immunological feature evaluation and immunotherapeutic outcome prediction at the molecular level.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233841
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3842: A Review on Autophagy in Orofacial Neuropathic

    • Authors: Mayank Shrivastava, Liang Ye
      First page: 3842
      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 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.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233842
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3843: The Role of Oxidative Stress in

    • Authors: Matthew Batty, Martin R. Bennett, Emma Yu
      First page: 3843
      Abstract: Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233843
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3844: Primary Investigation of Phenotypic Plasticity
           in Fritillaria cirrhosa Based on Metabolome and Transcriptome Analyses

    • Authors: Ye Wang, Huigan Xie, Tiechui Yang, Dan Gao, Xiwen Li
      First page: 3844
      Abstract: Phenotypic plasticity refers to the adaptability of an organism to a heterogeneous environment. In this study, the differential gene expression and compositional changes in Fritillaria cirrhosa during phenotypic plasticity were evaluated using transcriptomic and metabolomic analyses. The annotation profiles of 1696 differentially expressed genes from the transcriptome between abnormal and normal phenotypes revealed that the main annotation pathways were related to the biosynthesis of amino acids, ABC transporters, and plant–pathogen interactions. According to the metabolome, the abnormal phenotype had 36 upregulated amino acids, including tryptophan, proline, and valine, which had a 3.77-fold higher relative content than the normal phenotype. However, saccharides and vitamins were found to be deficient in the abnormal phenotypes. The combination profiles demonstrated that phenotypic plasticity may be an effective strategy for overcoming potential stress via the accumulation of amino acids and regulation of the corresponding genes and transcription factors. In conclusion, a pathogen attack on F. cirrhosa may promote the synthesis of numerous amino acids and transport them into the bulbs through ABC transporters, which may further result in phenotypic variation. Our results provide new insights into the potential mechanism of phenotypic changes.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233844
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3845: Stem-Cell-Derived β-Like Cells with a
           Functional PTPN2 Knockout Display Increased Immunogenicity

    • Authors: Taylor M. Triolo, J. Quinn Matuschek, Roberto Castro-Gutierrez, Ali H. Shilleh, Shane P. M. Williams, Maria S. Hansen, Kristen McDaniel, Jessie M. Barra, Aaron Michels, Holger A. Russ
      First page: 3845
      Abstract: Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233845
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3846: Transcriptomic Classification of Pituitary
           Neuroendocrine Tumors Causing Acromegaly

    • Authors: Julia Rymuza, Paulina Kober, Natalia Rusetska, Beata J. Mossakowska, Maria Maksymowicz, Aleksandra Nyc, Szymon Baluszek, Grzegorz Zieliński, Jacek Kunicki, Mateusz Bujko
      First page: 3846
      Abstract: Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors that co-express GIPR and NR5A1 (SF-1). SF-1 expression was verified with immunohistochemistry. Transcriptomic group 2 tumors are the most common (46%) and include mainly GNAS-mutated, densely granulated somatotroph and mixed PitNETs. They have a smaller size and express favorable prognosis-related genes. Transcriptomic group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly. Ghrelin signaling is implicated in their pathogenesis. They have an unfavorable gene expression profile and higher invasive growth rate.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233846
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3847: Relative Leukocyte Telomere Length and Genetic
           Variants in Telomere-Related Genes and Serum Levels Role in Age-Related
           Macular Degeneration

    • Authors: Alvita Vilkeviciute, Greta Gedvilaite, Mantas Banevicius, Loresa Kriauciuniene, Dalia Zaliuniene, Olivija Dobiliene, Rasa Liutkeviciene
      First page: 3847
      Abstract: Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development. Methods: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA). Results: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group. Conclusions: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233847
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3848: Dietary Choline Mitigates High-Fat
           Diet-Impaired Chylomicrons Assembly via UPRer Modulated by perk DNA

    • Authors: Zhen-Yu Bai, Hua Zheng, Zhi Luo, Christer Hogstrand, Ling-Jiao Wang, Yu-Feng Song
      First page: 3848
      Abstract: High-fat diets (HFD) lead to impairment of chylomicrons (CMs) assembly and adversely influence intestinal lipid homeostasis. However, the mechanisms of HFD impairing CMs assembly have yet to be fully understood. Additionally, although choline, as a lipid-lowering agent, has been widely used and its deficiency has been closely linked to non-alcoholic steatohepatitis (NASH), the contribution of choline by functioning as a methyl donor in alleviating HFD-induced intestinal lipid deposition is unknown. Thus, this study was conducted to determine the mechanism of HFD impairing CMs assembly and also tested the effect of choline acting as a methyl donor in this process. To this end, in this study, four diets (control, HFD, choline and HFD + choline diet) were fed to yellow catfish for 10 weeks in vivo and their intestinal epithelial cells were isolated and incubated for 36 h in fatty acids (FA) with or without choline solution combining si-perk transfection in vitro. The key findings from this study as follows: (1) HFD caused impairment of CMs assembly main by unfolded protein response (UPRer). HFD activated perk and then induced UPRer, which led to endoplasmic reticulum dysfunction and further impaired CMs assembly via protein–protein interactions between Perk and Apob48. (2) Choline inhibited the transcriptional expression level of perk via activating the −211 CpG methylation site, which initiated the subsequent ameliorating effect on HFD-impaired CMs assembly and intestinal lipid dysfunction. These results provide a new insight into direct crosstalk between UPRer and CMs assembly, and also emphasize the critical contribution of choline acting as a methyl donor and shed new light on choline-deficient diet-induced NASH.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233848
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3849: The Biological Effects of Compound Microwave
           Exposure with 2.8 GHz and 9.3 GHz on Immune System: Transcriptomic and
           Proteomic Analysis

    • Authors: Chuanfu Yao, Hui Wang, Liu Sun, Ke Ren, Ji Dong, Haoyu Wang, Jing Zhang, Xinping Xu, Binwei Yao, Hongmei Zhou, Li Zhao, Ruiyun Peng
      First page: 3849
      Abstract: It is well-known that microwaves produce both thermal and nonthermal effects. Microwave ablation can produce thermal effects to activate the body’s immune system and has been widely used in cancer therapy. However, the nonthermal effects of microwaves on the immune system are still largely unexplored. In the present study, we exposed rats to multifrequency microwaves of 2.8 GHz and 9.3 GHz with an average power density of 10 mW/cm2, which are widely used in our daily life, to investigate the biological effects on the immune system and its potential mechanisms. Both single-frequency microwaves and multifrequency microwaves caused obvious pathological alterations in the thymus and spleen at seven days after exposure, while multifrequency microwaves produced more pronounced injuries. Unexpectedly, multifrequency microwave exposure increased the number of both leukocytes and lymphocytes in the peripheral blood and upregulated the proportion of B lymphocytes among the total lymphocytes, indicating activation of the immune response. Our data also showed that the cytokines associated with the proliferation and activation of B lymphocytes, including interleukin (IL)-1α, IL-1β and IL-4, were elevated at six hours after exposure, which might contribute to the increase in B lymphocytes at seven days after exposure. Moreover, multifrequency microwave exposure upregulated the mRNA and protein expression of B cell activation-associated genes in peripheral blood. In addition to immune-associated genes, multifrequency microwaves mainly affected the expression of genes related to DNA duplication, cellular metabolism and signal transduction in the peripheral blood and spleen. In conclusion, multifrequency microwaves with 2.8 GHz and 9.3 GHz caused reversible injuries of the thymus and spleen but activated immune cells in the peripheral blood by upregulating mRNA and protein expression, as well as cytokine release. These results not only uncovered the biological effects of multifrequency microwave on the immune system, but also provide critical clues to explore the potential mechanisms.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233849
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3850: Intercommunication between Voltage-Gated
           Calcium Channels and Estrogen Receptor/Estrogen Signaling: Insights into
           Physiological and Pathological Conditions

    • Authors: Yashashwini Dinesh Subbamanda, Anamika Bhargava
      First page: 3850
      Abstract: Voltage-gated calcium channels (VGCCs) and estrogen receptors are important cellular proteins that have been shown to interact with each other across varied cells and tissues. Estrogen hormone, the ligand for estrogen receptors, can also exert its effects independent of estrogen receptors that collectively constitute non-genomic mechanisms. Here, we provide insights into the VGCC regulation by estrogen and the possible mechanisms involved therein across several cell types. Notably, most of the interaction is described in neuronal and cardiovascular tissues given the importance of VGCCs in these electrically excitable tissues. We describe the modulation of various VGCCs by estrogen known so far in physiological conditions and pathological conditions. We observed that in most in vitro studies higher concentrations of estrogen were used while a handful of in vivo studies used meager concentrations resulting in inhibition or upregulation of VGCCs, respectively. There is a need for more relevant physiological assays to study the regulation of VGCCs by estrogen. Additionally, other interacting receptors and partners need to be identified that may be involved in exerting estrogen receptor-independent effects of estrogen.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233850
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3851: Clinical Significance of Tie-2-Expressing
           Monocytes/Macrophages and Angiopoietins in the Progression of Ovarian

    • Authors: Wiktoria Skiba, Dorota Suszczyk, Anna Pawłowska, Karolina Włodarczyk, Anna Pańczyszyn, Iwona Wertel
      First page: 3851
      Abstract: Tumour growth and metastasis are specific to advanced stages of epithelial ovarian cancer (EOC). Tumour angiogenesis is an essential part of these processes. It is responsible for providing tumours with nutrients, metabolites, and cytokines and facilitates tumour and immune cell relocation. Destabilised vasculature, a distinctive feature of tumours, is also responsible for compromising drug delivery into the bulk. Angiogenesis is a complex process that largely depends on how the tumour microenvironment (TME) is composed and how a specific organ is formed. There are contrary reports on whether Tie-2-expressing monocytes/macrophages (TEMs) reported as the proangiogenic population of monocytes have any impact on tumour development. The aim of this paper is to summarise knowledge about ovarian-cancer-specific angiogenesis and the unique role of Tie-2-expressing monocytes/macrophages in this process. The significance of this cell subpopulation for the pathophysiology of EOC remains to be investigated.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233851
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3852: SERPINB2, an Early Responsive Gene to
           Epigallocatechin Gallate, Inhibits Migration and Promotes Apoptosis in
           Esophageal Cancer Cells

    • Authors: Zikai Chen, Yifu Wei, Yuzhong Zheng, Hui Zhu, Qian Teng, Xianglan Lin, Fengnian Wu, Fei Zhou
      First page: 3852
      Abstract: Esophageal cancer is a lethal disease that frequently occurs in developing countries, the incidence of which could be declined by drinking EGCG-enriched drinks or food. SERPINB2, whose complex functions and regulations are not yet fully understood, are induced by multiple inflammatory molecules and anti-tumor agents. Here, we identify 2444 EGCG-regulated genes in esophageal cancer cells, including SERPINB2. EGCG treatment recruits NF-κB at the promoter and enhancers of SERPINB2 and activates gene transcription, which is repressed by NF-κB knockdown or inhibition. Loss of SERPINB2 leads to a faster migration rate and less expression of Caspase-3 in cancer cells. Our study demonstrates that SERPINB2 is a new tumor-suppressor gene involved in cell movement and apoptosis and could be a therapeutic target for esophageal cancer.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233852
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3853: ARH Family of ADP-Ribose-Acceptor Hydrolases

    • Authors: Hiroko Ishiwata-Endo, Jiro Kato, Sachiko Yamashita, Chanbora Chea, Kazushige Koike, Duck-Yeon Lee, Joel Moss
      First page: 3853
      Abstract: The ARH family of ADP-ribose-acceptor hydrolases consists of three 39-kDa members (ARH1-3), with similarities in amino acid sequence. ARH1 was identified based on its ability to cleave ADP-ribosyl-arginine synthesized by cholera toxin. Mammalian ADP-ribosyltransferases (ARTCs) mimicked the toxin reaction, with ARTC1 catalyzing the synthesis of ADP-ribosyl-arginine. ADP-ribosylation of arginine was stereospecific, with β-NAD+ as substrate and, α-anomeric ADP-ribose-arginine the reaction product. ARH1 hydrolyzed α-ADP-ribose-arginine, in addition to α-NAD+ and O-acetyl-ADP-ribose. Thus, ADP-ribose attached to oxygen-containing or nitrogen-containing functional groups was a substrate. Arh1 heterozygous and knockout (KO) mice developed tumors. Arh1-KO mice showed decreased cardiac contractility and developed myocardial fibrosis. In addition to Arh1-KO mice showed increased ADP-ribosylation of tripartite motif-containing protein 72 (TRIM72), a membrane-repair protein. ARH3 cleaved ADP-ribose from ends of the poly(ADP-ribose) (PAR) chain and released the terminal ADP-ribose attached to (serine)protein. ARH3 also hydrolyzed α-NAD+ and O-acetyl-ADP-ribose. Incubation of Arh3-KO cells with H2O2 resulted in activation of poly-ADP-ribose polymerase (PARP)-1, followed by increased nuclear PAR, increased cytoplasmic PAR, leading to release of Apoptosis Inducing Factor (AIF) from mitochondria. AIF, following nuclear translocation, stimulated endonucleases, resulting in cell death by Parthanatos. Human ARH3-deficiency is autosomal recessive, rare, and characterized by neurodegeneration and early death. Arh3-KO mice developed increased brain infarction following ischemia-reperfusion injury, which was reduced by PARP inhibitors. Similarly, PARP inhibitors improved survival of Arh3-KO cells treated with H2O2. ARH2 protein did not show activity in the in vitro assays described above for ARH1 and ARH3. ARH2 has a restricted tissue distribution, with primary involvement of cardiac and skeletal muscle. Overall, the ARH family has unique functions in biological processes and different enzymatic activities.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233853
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3854: HyClear: A Novel Tissue Clearing Solution for
           One-Step Clearing of Microtissues

    • Authors: S. Soroush Nasseri, Erika M. J. Siren, Jayachandran N. Kizhakkedathu, Karen Cheung
      First page: 3854
      Abstract: 3-D cell cultures are being increasingly used as in vitro models are capable of better mimicry of in vivo tissues, particularly in drug screenings where mass transfer limitations can affect the cancer biology and response to drugs. Three-dimensional microscopy techniques, such as confocal and multiphoton microscopy, have been used to elucidate data from 3-D cell cultures and whole organs, but their reach inside the 3-D tissues is restrained by the light scattering of the tissues, limiting their effective reach to 100–200 µm, which is simply not enough. Tissue clearing protocols, developed mostly for larger specimens usually involve multiple steps of viscous liquid submersion, and are not easily adaptable for much smaller spheroids and organoids. In this work, we have developed a novel tissue clearing solution tailored for small spheroids and organoids. Our tissue clearing protocol, called HyClear, uses a mixture of DMSO, HPG and urea to allow for one-step tissue clearing of spheroids and organoids, and is compatible with high-throughput screening studies due to its speed and simplicity. We have shown that our tissue clearing agent is superior to many of the commonly used tissue clearing agents and allows for elucidating better quality data from drug screening experiments.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233854
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3855: Induction of Cardiac Pathology: Endogenous
           versus Exogenous Nrf2 Upregulation

    • Authors: Bryan J. Mathis, Hideyuki Kato, Yuji Hiramatsu
      First page: 3855
      Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the endogenous antioxidant response to reactive oxygen species as well as a controller of Phase II detoxification in response to xenobiotics. This amenity to specific external manipulation exploits the binding affinity of Nrf2 for its constitutive repressor and degradation facilitator Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1). Derived from both natural and synthesized origins, these compounds have been extensively tested without definitive beneficial results. Unfortunately, multiple terminated trials have shown a negative side to Nrf2 with regard to cardiac pathologies while animal-based studies have demonstrated cardiomyocyte hypertrophy and heart failure after chronic Nrf2 upregulation. Putatively based on autophagic control of Nrf2 activity-modulating upstream factors, new evidence of miRNA involvement has added complexity to this mechanism. What follows is an extensive survey of Nrf2-regulating exogenous compounds that may promote cardiomyopathy, clinical trial evidence, and a comparison to exercise-induced factors that also upregulate Nrf2 while preventing cardiac pathologies.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233855
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3856: Identification and Functional Characterization
           of the Transcription Factors AhR/ARNT in Dendroctonus armandi

    • Authors: Bin Liu, Hui Chen
      First page: 3856
      Abstract: The aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) belong to the bHLH-PAS (basic Helix–Loop–Helix–Period/ARNT/Single-minded) family of transcription factors, which participate in the sensing and transmitting stimuli of exogenous and endogenous chemical substances, and subsequently activates genes transcription involved in various detoxification and physiological functions. However, they have not been identified in Dendroctonus armandi, and their roles in the detoxification metabolism are unclear. In the present study, AhR and ARNT of D. armandi were characterized. Spatiotemporal expression profiling indicated that DaAhR and DaARNT were highly expressed in the adult and larval stages of D. armandi and mainly expressed in the midgut and Malpighian tubules of adults. Additionally, the expression of DaAhR and DaARNT significantly increased after exposure to (−)-𝛽-pinene, (+)-3-carene, and (±)-limonene. Silencing DaAhR and DaARNT increased the susceptibility of D. armandi to (−)-𝛽-pinene, (+)-3-carene, and (±)-limonene, and the activities of detoxification enzyme were also remarkably reduced. Moreover, DaCYP6DF1 and DaGSTs2 were significantly down-regulated after injections of dsAhR and dsARNT in the male and female adults, with the expression of DaCYP6DF1 decreasing by higher than 70%. The present study revealed that the transcription factors AhR and ARNT of D. armandi were induced by terpenoids and participated in the regulation of DaCYP6DF1 expression, which was associated with D. armandi’s susceptibility to (−)-𝛽-pinene and (±)-limonene. These results may provide a theoretical basis for the integrated control of D. armandi and improve our comprehension of insect toxicology.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233856
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3857: CAF-Released Exosomal miR-20a-5p Facilitates
           HCC Progression via the LIMA1-Mediated β-Catenin Pathway

    • Authors: Yong Qi, Haibo Wang, Qikun Zhang, Zhiqiang Liu, Tianbing Wang, Zhengsheng Wu, Wenyong Wu
      First page: 3857
      Abstract: Currently, exosomes derived from Cancer-associated fibroblast (CAF) have reportedly been involved in regulating hepatocellular carcinoma (HCC) tumour microenvironment (TME). LIM domain and actin binding 1 (LIMA1) is an actin-binding protein that is involved in controlling the biological behaviour and progression of specific solid tumours. We aimed to determine the effect of LIMA1 and exosome-associated miR-20a-5p in HCC development. LIMA1 and miR-20a-5p expression levels were examined by real-time quantitative PCR (qRT-PCR), western blotting or immunohistochemistry (IHC). Functional experiments, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) assays, colony formation assays, wound healing assays, and Transwell invasion assays, were performed to investigate the effect of LIMA1 and miR-20a-5p. A dual-luciferase reporter gene assay was performed to confirm the interaction of miR-20a-5p and LIMA1. Exosomes were characterised by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. We noted that LIMA1 was downregulated in human HCC tissues and cells and remarkably correlated with overall survival (OS) and recurrence-free survival (RFS). LIMA1 overexpression suppressed HCC cell proliferation and metastasis in vitro and in vivo, while LIMA1 knockdown had the opposite effects. A mechanistic investigation showed that LIMA1 inhibited the Wnt/β-catenin signalling pathway by binding to BMI1 and inducing its destabilisation. Additionally, we found that LIMA1 expression in HCC cells could be suppressed by transferring CAF-derived exosomes harbouring oncogenic miR-20a-5p. In summary, LIMA1 is a tumour suppressor that inhibits the Wnt/β-catenin signalling pathway and is downregulated by CAF-derived exosomes carrying oncogenic miR-20a-5p in HCC.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233857
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3858: Advances in Musculoskeletal Cell Therapy:
           Basic Science and Translational Approaches

    • Authors: Enrico Ragni, Alessandra Colombini, Silvia Lopa
      First page: 3858
      Abstract: Nowadays, the real need in orthopedic research is to strictly validate advanced regenerative medicine approaches in preclinical models, with the hope that this unique and straightforward approach can facilitate a safe and effective translation into everyday clinical practice [...]
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233858
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3859: MAGOH and MAGOHB Knockdown in Melanoma Cells
           Decreases Nonsense-Mediated Decay Activity and Promotes Apoptosis via
           Upregulation of GADD45A

    • Authors: Agnes Soederberg, Tina Meißgeier, Anja Katrin Bosserhoff, Lisa Linck-Paulus
      First page: 3859
      Abstract: Cutaneous malignant melanoma is a highly proliferative and aggressive skin cancer with a steadily increasing incidence and a low long-term survival rate after metastatic progression. The protein MAGOH and its highly identical homologue MAGOHB are core components of the exon junction complex (EJC), which regulates splicing, stability and translation of mRNAs. The EJC, and especially MAGOH, has been shown to be involved in the development and progression of several cancers. In melanoma, the expression and function of both homologues remain essentially unexplored. This study identifies high MAGOH and MAGOHB protein expression in cutaneous melanoma cell lines and patient derived tissue samples. An siRNA-mediated knockdown of MAGOH significantly inhibits melanoma cell proliferation. The loss of MAGOH does not affect cell cycle progression, but induces apoptosis, an effect that is enhanced by a simultaneous knockdown of MAGOH and MAGOHB. MAGOH and MAGOHB do not influence the expression of the pro-apoptotic protein Bcl-XS or exon skipping. However, the knockdown of MAGOH and MAGOHB strongly decreases nonsense-mediated decay (NMD) activity, leading to an upregulation of the pro-apoptotic protein GADD45A. In conclusion, simultaneous inhibition of MAGOH and MAGOHB expression substantially affects cell survival, indicating both MAGOH homologues as promising new targets for the treatment of melanoma.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233859
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3860: GABAA and GABAB Receptors Mediate GABA-Induced

    • Authors: Sharon Negri, Francesca Scolari, Mauro Vismara, Valentina Brunetti, Pawan Faris, Giulia Terribile, Giulio Sancini, Roberto Berra-Romani, Francesco Moccia
      First page: 3860
      Abstract: Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233860
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3861: TGF-β2 Regulates Transcription of the
           K+/Cl− Cotransporter 2 (KCC2) in Immature Neurons and Its
           Phosphorylation at T1007 in Differentiated Neurons

    • Authors: Anastasia Rigkou, Attila Magyar, Jan Manuel Speer, Eleni Roussa
      First page: 3861
      Abstract: KCC2 mediates extrusion of K+ and Cl− and assuresthe developmental “switch” in GABA function during neuronal maturation. However, the molecular mechanisms underlying KCC2 regulation are not fully elucidated. We investigated the impact of transforming growth factor beta 2 (TGF-β2) on KCC2 during neuronal maturation using quantitative RT-PCR, immunoblotting, immunofluorescence and chromatin immunoprecipitation in primary mouse hippocampal neurons and brain tissue from Tgf-β2-deficient mice. Inhibition of TGF-β/activin signaling downregulates Kcc2 transcript in immature neurons. In the forebrain of Tgf-β2−/− mice, expression of Kcc2, transcription factor Ap2β and KCC2 protein is downregulated. AP2β binds to Kcc2 promoter, a binding absent in Tgf-β2−/−. In hindbrain/brainstem tissue of Tgf-β2−/− mice, KCC2 phosphorylation at T1007 is increased and approximately half of pre-Bötzinger-complex neurons lack membrane KCC2 phenotypes rescued through exogenous TGF-β2. These results demonstrate that TGF-β2 regulates KCC2 transcription in immature neurons, possibly acting upstream of AP2β, and contributes to the developmental dephosphorylation of KCC2 at T1007. The present work suggests multiple and divergent roles for TGF-β2 on KCC2 during neuronal maturation and provides novel mechanistic insights for TGF-β2-mediated regulation of KCC2 gene expression, posttranslational modification and surface expression. We propose TGF-β2 as a major regulator of KCC2 with putative implications for pathophysiological conditions.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233861
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3862: High-Content RNAi Phenotypic Screening Unveils
           the Involvement of Human Ubiquitin-Related Enzymes in Late Cytokinesis

    • Authors: Mikaël Boullé, Laurianne Davignon, Keïs Nabhane Saïd Halidi, Salomé Guez, Emilie Giraud, Marcel Hollenstein, Fabrice Agou
      First page: 3862
      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 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.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233862
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3863: Cell Type-Specific Metabolic Response to Amino
           Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1

    • Authors: Biljana Blagojevic, Fadi Almouhanna, Gernot Poschet, Stefan Wölfl
      First page: 3863
      Abstract: Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233863
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3864: Restoring Age-Related Cognitive Decline
           through Environmental Enrichment: A Transcriptomic Approach

    • Authors: Silvio Schmidt, Madlen Haase, Lena Best, Marco Groth, Julia Lindner, Otto W. Witte, Christoph Kaleta, Christiane Frahm
      First page: 3864
      Abstract: Cognitive decline is one of the greatest health threats of old age and the maintenance of optimal brain function across a lifespan remains a big challenge. The hippocampus is considered particularly vulnerable but there is cross-species consensus that its functional integrity benefits from the early and continuous exercise of demanding physical, social and mental activities, also referred to as environmental enrichment (EE). Here, we investigated the extent to which late-onset EE can improve the already-impaired cognitive abilities of lifelong deprived C57BL/6 mice and how it affects gene expression in the hippocampus. To this end, 5- and 24-month-old mice housed in standard cages (5mSC and 24mSC) and 24-month-old mice exposed to EE in the last 2 months of their life (24mEE) were subjected to a Barnes maze task followed by next-generation RNA sequencing of the hippocampal tissue. Our analyses showed that late-onset EE was able to restore deficits in spatial learning and short-term memory in 24-month-old mice. These positive cognitive effects were reflected by specific changes in the hippocampal transcriptome, where late-onset EE affected transcription much more than age (24mSC vs. 24mEE: 1311 DEGs, 24mSC vs. 5mSC: 860 DEGs). Remarkably, a small intersection of 72 age-related DEGs was counter-regulated by late-onset EE. Of these, Bcl3, Cttnbp2, Diexf, Esr2, Grb10, Il4ra, Inhba, Rras2, Rps6ka1 and Socs3 appear to be particularly relevant as key regulators involved in dendritic spine plasticity and in age-relevant molecular signaling cascades mediating senescence, insulin resistance, apoptosis and tissue regeneration. In summary, our observations suggest that the brains of aged mice in standard cage housing preserve a considerable degree of plasticity. Switching them to EE proved to be a promising and non-pharmacological intervention against cognitive decline.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233864
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3865: Advances in Innate Immunity to Overcome Immune
           Rejection during Xenotransplantation

    • Authors: Tian-Yu Lu, Xue-Ling Xu, Xu-Guang Du, Jin-Hua Wei, Jia-Nan Yu, Shou-Long Deng, Chuan Qin
      First page: 3865
      Abstract: Transplantation is an effective approach for treating end-stage organ failure. There has been a long-standing interest in xenotransplantation as a means of increasing the number of available organs. In the past decade, there has been tremendous progress in xenotransplantation accelerated by the development of rapid gene-editing tools and immunosuppressive therapy. Recently, the heart and kidney from pigs were transplanted into the recipients, which suggests that xenotransplantation has entered a new era. The genetic discrepancy and molecular incompatibility between pigs and primates results in barriers to xenotransplantation. An increasing body of evidence suggests that innate immune responses play an important role in all aspects of the xenogeneic rejection. Simultaneously, the role of important cellular components like macrophages, natural killer (NK) cells, and neutrophils, suggests that the innate immune response in the xenogeneic rejection should not be underestimated. Here, we summarize the current knowledge about the innate immune system in xenotransplantation and highlight the key issues for future investigations. A better understanding of the innate immune responses in xenotransplantation may help to control the xenograft rejection and design optimal combination therapies.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233865
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3866: Mitochondrial Permeability Transition

    • Authors: Paolo Bernardi, Evgeny Pavlov
      First page: 3866
      Abstract: The mitochondrial permeability transition (PT) is a phenomenon that can be broadly defined as an increase in the permeability of the mitochondrial inner membrane [...]
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233866
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3867: Differentially Expressed Cell Cycle Genes and
           STAT1/3-Driven Multiple Cancer Entanglement in Psoriasis, Coupled with
           Other Comorbidities

    • Authors: Subhashini Dorai, Daniel Alex Anand
      First page: 3867
      Abstract: Psoriasis is a persistent T-cell-supported inflammatory cutaneous disorder, which is defined by a significant expansion of basal cells in the epidermis. Cell cycle and STAT genes that control cell cycle progression and viral infection have been revealed to be comorbid with the development of certain cancers and other disorders, due to their abnormal or scanty expression. The purpose of this study is to evaluate the expression of certain cell cycle and STAT1/3 genes in psoriasis patients and to determine the types of comorbidities associated with these genes. To do so, we opted to adopt the in silico methodology, since it is a quick and easy way to discover any potential comorbidity risks that may exist in psoriasis patients. With the genes collected from early research groups, protein networks were created in this work using the NetworkAnalyst program. The crucial hub genes were identified by setting the degree parameter, and they were then used in gene ontology and pathway assessments. The transcription factors that control the hub genes were detected by exploring TRRUST, and DGIdb was probed for remedies that target transcription factors and hubs. Using the degree filter, the first protein subnetwork produced seven hub genes, including STAT3, CCNB1, STAT1, CCND1, CDC20, HSPA4, and MAD2L1. The hub genes were shown to be implicated in cell cycle pathways by the gene ontology and Reactome annotations. The former four hubs were found in signaling pathways, including prolactin, FoxO, JAK/STAT, and p53, according to the KEGG annotation. Furthermore, they enhanced several malignancies, including pancreatic cancer, Kaposi’s sarcoma, non-small cell lung cancer, and acute myeloid leukemia. Viral infections, including measles, hepatitis C, Epstein–Barr virus, and HTLV-1 and viral carcinogenesis were among the other susceptible diseases. Diabetes and inflammatory bowel disease were conjointly annotated. In total, 129 medicines were discovered in DGIdb to be effective against the transcription factors BRCA1, RELA, TP53, and MYC, as opposed to 10 medications against the hubs, STAT3 and CCND1, in tandem with 8 common medicines. The study suggests that the annotated medications should be tested in suitable psoriatic cell lines and animal models to optimize the drugs used based on the kind, severity, and related comorbidities of psoriasis. Furthermore, a personalized medicine protocol must be designed for each psoriasis patient that displays different comorbidities.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233867
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3868: Translation Potential and Challenges of In
           Vitro and Murine Models in Cancer Clinic

    • Authors: Yuan Long, Bin Xie, Hong C. Shen, Danyi Wen
      First page: 3868
      Abstract: As one of the leading causes of death from disease, cancer continues to pose a serious threat to human health globally. Despite the development of novel therapeutic regimens and drugs, the long-term survival of cancer patients is still very low, especially for those whose diagnosis is not caught early enough. Meanwhile, our understanding of tumorigenesis is still limited. Suitable research models are essential tools for exploring cancer mechanisms and treatments. Herein we review and compare several widely used in vitro and in vivo murine cancer models, including syngeneic tumor models, genetically engineered mouse models (GEMM), cell line-derived xenografts (CDX), patient-derived xenografts (PDX), conditionally reprogrammed (CR) cells, organoids, and MiniPDX. We will summarize the methodology and feasibility of various models in terms of their advantages and limitations in the application prospects for drug discovery and development and precision medicine.
      Citation: Cells
      PubDate: 2022-11-30
      DOI: 10.3390/cells11233868
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3869: The Protective Role of Microglial PPARα
           in Diabetic Retinal Neurodegeneration and Neurovascular Dysfunction

    • Authors: Tian Yuan, Lijie Dong, Elizabeth A. Pearsall, Kelu Zhou, Rui Cheng, Jian-Xing Ma
      First page: 3869
      Abstract: Microglial activation and subsequent pathological neuroinflammation contribute to diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological microgliosis, remain incompletely understood. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism. The present study aimed to determine if PPARα affects pathological microgliosis in DR. In global Pparα mice, retinal microglia exhibited decreased structural complexity and enlarged cell bodies, suggesting microglial activation. Microglia-specific conditional Pparα−/− (PCKO) mice showed decreased retinal thickness as revealed by optical coherence tomography. Under streptozotocin (STZ)-induced diabetes, diabetic PCKO mice exhibited decreased electroretinography response, while diabetes-induced retinal dysfunction was alleviated in diabetic microglia-specific Pparα-transgenic (PCTG) mice. Additionally, diabetes-induced retinal pericyte loss was exacerbated in diabetic PCKO mice and alleviated in diabetic PCTG mice. In cultured microglial cells with the diabetic stressor 4-HNE, metabolic flux analysis demonstrated that Pparα ablation caused a metabolic shift from oxidative phosphorylation to glycolysis. Pparα deficiency also increased microglial STING and TNF-α expression. Taken together, these findings revealed a critical role for PPARα in pathological microgliosis, neurodegeneration, and vascular damage in DR, providing insight into the underlying molecular mechanisms of microgliosis in this context and suggesting microglial PPARα as a potential therapeutic target.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233869
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3870: Orphan Nuclear Receptor Nur77 Mediates the
           Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of
           Cryptomeridiol in Hepatocellular Carcinoma

    • Authors: Xudan Li, Quancheng Chen, Jie Liu, Shenjin Lai, Minda Zhang, Tidong Zhen, Hongyu Hu, Xiang Gao, Alice S. T. Wong, Jin-Zhang Zeng
      First page: 3870
      Abstract: Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpenoid derivative isolated from traditional Chinese medicine Magnolia officinalis, has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1α-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Δψm). The Bkh126-induced aggravation of ER stress and mitochondrial dysfunction result in increased cytotoxic product of reactive oxygen species (ROS). The in vivo anti-HCC activity of Bkh126 is superior to that of sorafenib, currently used to treat advanced HCC. Our study shows that Bkh126 induces Nur77 to connect ER stress to mitochondria-mediated cell killing. The identification of Nur77 as a molecular target of Bhk126 provides a basis for improving the leads for the further development of anti-HCC drugs.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233870
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3871: Drosophila melanogaster Oocytes after Space
           Flight: The Early Period of Adaptation to the Force of Gravity

    • Authors: Irina V. Ogneva, Maria A. Golubkova, Nikolay S. Biryukov, Oleg V. Kotov
      First page: 3871
      Abstract: The effect of space flight factors and the subsequent adaptation to the Earth’s gravity on oocytes is still poorly understood. Studies of mammalian oocytes in space present significant technical difficulties; therefore, the fruit fly Drosophila melanogaster is a convenient test subject. In this study, we analyzed the structure of the oocytes of the fruit fly Drosophila melanogaster, the maturation of which took place under space flight conditions (the “Cytomehanarium” experiment on the Russian Segment of the ISS during the ISS-67 expedition). The collection of the oocytes began immediately after landing and continued for 12 h. The flies were then transferred onto fresh agar plates and oocyte collection continued for the subsequent 12 h. The stiffness of oocytes was determined by atomic force microscopy and the content of the cytoskeletal proteins by Western blotting. The results demonstrated a significant decrease in the stiffness of oocytes in the flight group compared to the control (26.5 ± 1.1 pN/nm vs. 31.0 ± 1.8 pN/nm) against the background of a decrease in the content of some cytoskeletal proteins involved in the formation of microtubules and microfilaments. This pattern of oocyte structure leads to the disruption of cytokinesis during the cleavage of early embryos.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233871
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3872: A Spontaneous Inversion of the X Chromosome
           Heterochromatin Provides a Tool for Studying the Structure and Activity of
           the Nucleolus in Drosophila melanogaster

    • Authors: Tatyana D. Kolesnikova, Mikhail S. Klenov, Alina R. Nokhova, Sergey A. Lavrov, Galina V. Pokholkova, Veit Schubert, Svetlana V. Maltseva, Kevin R. Cook, Michael J. Dixon, Igor F. Zhimulev
      First page: 3872
      Abstract: The pericentromeric heterochromatin is largely composed of repetitive sequences, making it difficult to analyze with standard molecular biological methods. At the same time, it carries many functional elements with poorly understood mechanisms of action. The search for new experimental models for the analysis of heterochromatin is an urgent task. In this work, we used the Rif1 mutation, which suppresses the underreplication of all types of repeated sequences, to analyze heterochromatin regions in polytene chromosomes of Drosophila melanogaster. In the Rif1 background, we discovered and described in detail a new inversion, In(1)19EHet, which arose on a chromosome already carrying the In(1)sc8 inversion and transferred a large part of X chromosome heterochromatin, including the nucleolar organizer to a new euchromatic environment. Using nanopore sequencing and FISH, we have identified the eu- and heterochromatin breakpoints of In(1)19EHet. The combination of the new inversion and the Rif1 mutation provides a promising tool for studies of X chromosome heterochromatin structure, nucleolar organization, and the nucleolar dominance phenomenon. In particular, we found that, with the complete polytenization of rDNA repeats, the nucleolus consists of a cloud-like structure corresponding to the classical nucleolus of polytene chromosomes, as well as an unusual intrachromosomal structure containing alternating transcriptionally active and inactive regions.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233872
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3873: The Autocrine Role of Placental Extracellular
           Vesicles from Missed Miscarriage in Causing Senescence: Possible
           Pathogenesis of Missed Miscarriage

    • Authors: Yi Zhang, Yunhui Tang, Yang Liu, Jiayi Wang, Ye Shen, Xinyi Sun, Matthew Kang, Min Zhao, Qi Chen
      First page: 3873
      Abstract: Placental dysfunction, including senescent changes, is associated with the pathogenesis of missed miscarriage, although the underlying mechanism is unclear. Increasing evidence indicates that placenta-specific miRNAs are packaged in extracellular vesicles (EVs) from placental syncytiotrophoblasts and are released into the maternal circulation. Aberrant cargos including miRNAs in placental EVs have been reported to be associated with the pathogenesis of complicated pregnancies. In this study, we compared the miRNA profiles in EVs derived from missed miscarriage and healthy placentae and investigated possible biological pathways which may be involved in senescence, one cause of missed miscarriage. The total concentration of RNA in placental EVs was not different between the two groups. However, there were 54 and 94 differentially expressed miRNAs in placental large and small EVs from missed miscarriage compared to EVs from healthy controls. The aberrantly expressed miRNAs seen in placental EVs were also observed in missed miscarriage placentae. Gene enrichment analysis showed that some of those differentially expressed miRNAs are involved in cellular senescence, endocytosis, cell cycle and endocrine resistance. Furthermore, transfection of trophoblasts by a single senescence-associated miRNA that was differentially expressed in placental EVs derived from missed miscarriage did not cause trophoblast dysfunction. In contrast, EVs derived from missed miscarriage placenta induced senescent changes in the healthy placenta. Our data suggested that a complex of placental EVs, rather than a few differentially expressed miRNAs in placental EVs derived from missed miscarriage placentae could contribute in an autocrine manner to placental senescence, one of the causes of missed miscarriage.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233873
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3874: Development of a Lung Vacancy Mouse Model
           through CRISPR/Cas9-Mediated Deletion of Thyroid Transcription Factor 1
           Exon 2

    • Authors: Lihua Zhao, Meishuang Li, Zhibao Yin, Limin Lv, Meng Zhou, Yixi Wang, Manling Zhang, Tianxu Guo, Xiyun Guo, Han Liu, Linxin Cheng, Xiubin Liang, Shuguang Duo, Rongfeng Li
      First page: 3874
      Abstract: A developmental niche vacancy in host embryos is necessary for stem cell complementation-based organ regeneration (SCOG). Thyroid transcription factor 1 (TTF-1) is a tissue-specific transcription factor that regulates the embryonic development and differentiation of the thyroid and, more importantly, lungs; thus, it has been considered as a master gene to knockout in order to develop a lung vacancy host. TTF-1 knockout mice were originally produced by inserting a stop codon in Exon 3 of the gene (E3stop) through embryonic stem cell-based homologous recombination. The main problems of utilizing E3stop host embryos for lung SCOG are that these animals all have a tracheoesophageal fistula (TEF), which cannot be corrected by donor stem cells, and most of them have monolateral sac-like lungs. To improve the mouse model towards achieving SCOG-based lung generation, in this project, we used the CRISPR/Cas9 tool to remove Exon 2 of the gene by zygote microinjection and successfully produced TTF-1 knockout (E2del) mice. Similar to E3stop, E2del mice are birth-lethal due to retarded lung development with sac-like lungs and only a rudimentary bronchial tree, increased basal cells but without alveolar type II cells and blood vessels, and abnormal thyroid development. Unlike E3stop, 57% of the E2del embryos presented type I tracheal agenesis (TA, a kind of human congenital malformation) with a shortened trachea and clear separations of the trachea and esophagus, while the remaining 43% had TEF. Furthermore, all the E2del mice had bilateral sac-like lungs. Both TA and bilateral sac-like lungs are preferred in SCOG. Our work presents a new strategy for producing SCOG host embryos that may be useful for lung regeneration.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233874
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3875: Application of ALFA-Tagging in the Nematode
           Model Organisms Caenorhabditis elegans and Pristionchus pacificus

    • Authors: Catia Igreja, Tobias Loschko, Alejandra Schäfer, Radhika Sharma, Shiela Pearl Quiobe, Elbin Aloshy, Hanh Witte, Ralf J. Sommer
      First page: 3875
      Abstract: The detection, manipulation and purification of proteins is key in modern life sciences studies. To achieve this goal, a plethora of epitope tags have been employed in model organisms from bacteria to humans. Recently, the introduction of the rationally designed ALFA-tag resulted in a highly versatile tool with a very broad spectrum of potential applications. ALFA-tagged proteins can be detected by nanobodies, the single-domain antibodies of camelids, allowing for super-resolution microscopy and immunoprecipitation in biochemical applications. Here, we introduce ALFA-tagging into the two nematode model organisms Caenorhabditis elegans and Pristionchus pacificus. We show that the introduction of the DNA sequence, corresponding to the 13 amino acid sequence of the ALFA-tag, can easily be accommodated by CRISPR engineering. We provide examples of high-resolution protein expression in both nematodes. Finally, we use the GW182 ortholog Ppa-ain-1 to show successful pulldowns in P. pacificus. Thus, the ALFA-tag represents a novel epitope tag for nematode research with a broad spectrum of applications.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233875
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3876: The Expression Pattern of Adhesion G
           Protein-Coupled Receptor F5 Is Related to Cell Adhesion and Metastatic
           Pathways in Colorectal Cancer—Comprehensive Study Based on In Silico

    • Authors: Huining Kang, Jakub Fichna, Ksenia Matlawska-Wasowska, Damian Jacenik
      First page: 3876
      Abstract: Adhesion G protein-coupled receptor F5 (ADGRF5) is involved inthe neoplastic transformation of some cancer types. However, the significance of ADGRF5 expression signature and the impact of signaling pathways mediated by ADGRF5 during neoplastic transformation of the colon and colorectal cancer (CRC) progression has been poorly examined. Using Gene Expression Omnibus and The Cancer Genome Atlas datasets, we showed that ADGRF5 is overexpressed in the colons of patients with CRC. In line, combined analysis of ADGRF5 expression with clinical characterization revealed an increased expression of ADGRF5 in patients with more advanced stages of CRC compared to patients with early stages of CRC. The Spearman correlation analysis documented numerous genes positively and negatively correlated with the expression pattern of ADGRF5 in the colon of patients with CRC. In the colon of CRC patients, the expression signature of ADGRF5 was associated with genes participating in phosphatidylinositol 3-kinase/Akt, focal adhesion, cell adhesion molecules, and ribosome signaling pathways. Of note, ADGRF5 expression correlated with the levels of tumor-infiltrating immune cells in the colon of CRC patients. Moreover, we found that CRC patients with high expression of ADGRF5 had a significantly lower probability of overall survival and disease-free survival. In conclusion, our results support the prognostic value of ADGRF5 and its potent therapeutic implication in CRC.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233876
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3877: The BRCAness Landscape of Cancer

    • Authors: Maoni Guo, San Ming Wang
      First page: 3877
      Abstract: BRCAness refers to the damaged homologous recombination (HR) function due to the defects in HR-involved non-BRCA1/2 genes. BRCAness is the important marker for the use of synthetic lethal-based PARP inhibitor therapy in breast and ovarian cancer treatment. The success provides an opportunity of applying PARP inhibitor therapy to treat other cancer types with BRCAness features. However, systematic knowledge is lack for BRCAness in different cancer types beyond breast and ovarian cancer. We performed a comprehensive characterization for 40 BRCAness-related genes in 33 cancer types with over 10,000 cancer cases, including pathogenic variation, homozygotic deletion, promoter hypermethylation, gene expression, and clinical correlation of BRCAness in each cancer type. Using BRCA1/BRCA2 mutated breast and ovarian cancer as the control, we observed that BRCAness is widely present in multiple cancer types. Based on the sum of the BRCAneass features in each cancer type, we identified the following 21 cancer types as the potential targets for PARPi therapy: adrenocortical carcinoma, bladder urothelial carcinoma, brain lower grade glioma, colon adenocarcinoma, esophageal carcinoma, head and neck squamous carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, rectum adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, uterine carcinosarcoma, and uterine corpus endometrial carcinoma.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233877
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3878: Normoxic HIF-1α Stabilization Caused by
           Local Inflammatory Factors and Its Consequences in Human Coronary Artery
           Endothelial Cells

    • Authors: Mohsen Abdi Sarabi, Alireza Shiri, Mahyar Aghapour, Charlotte Reichardt, Sabine Brandt, Peter R. Mertens, Senad Medunjanin, Dunja Bruder, Ruediger C. Braun-Dullaeus, Sönke Weinert
      First page: 3878
      Abstract: Knowledge about normoxic hypoxia-inducible factor (HIF)-1α stabilization is limited. We investigated normoxic HIF-1α stabilization and its consequences using live cell imaging, immunoblotting, Bio-Plex multiplex immunoassay, immunofluorescence staining, and barrier integrity assays. We demonstrate for the first time that IL-8 and M-CSF caused HIF-1α stabilization and translocation into the nucleus under normoxic conditions in both human coronary endothelial cells (HCAECs) and HIF-1α-mKate2-expressing HEK-293 cells. In line with the current literature, our data show significant normoxic HIF-1α stabilization caused by TNF-α, INF-γ, IL-1β, and IGF-I in both cell lines, as well. Treatment with a cocktail consisting of TNF-α, INF-γ, and IL-1β caused significantly stronger HIF-1α stabilization in comparison to single treatments. Interestingly, this cumulative effect was not observed during simultaneous treatment with IL-8, M-CSF, and IGF-I. Furthermore, we identified two different kinetics of HIF-1α stabilization under normoxic conditions. Our data demonstrate elevated protein levels of HIF-1α-related genes known to be involved in the development of atherosclerosis. Moreover, we demonstrate an endothelial barrier dysfunction in HCAECs upon our treatments and during normoxic HIF-1α stabilization comparable to that under hypoxia. This study expands the knowledge of normoxic HIF-1α stabilization and activation and its consequences on the endothelial secretome and barrier function. Our data imply an active role of HIF-1α in vivo in the vasculature in the absence of hypoxia.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233878
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3879: Mesenchymal Stem Cell-Derived Apoptotic
           Bodies: Biological Functions and Therapeutic Potential

    • Authors: Huixue Tang, Huikun Luo, Zihan Zhang, Di Yang
      First page: 3879
      Abstract: Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells with self-renewal ability and multipotency of osteogenic, chondrogenic, and adipogenic differentiation. MSCs have appeared as a promising approach for tissue regeneration and immune therapies, which are attributable not only to their differentiation into the desired cells but also to their paracrine secretion. MSC-sourced secretome consists of soluble components including growth factors, chemokines, cytokines, and encapsulated extracellular vesicles (EVs). Apoptotic bodies (ABs) are large EVs (diameter 500𠀓2000 nm) harboring a variety of cellular components including microRNA, mRNA, DNA, protein, and lipids related to the characteristics of the originating cell, which are generated during apoptosis. The released ABs as well as the genetic information they carry are engulfed by target cells such as macrophages, dendritic cells, epithelial cells, and fibroblasts, and subsequently internalized and degraded in the lysosomes, suggesting their ability to facilitate intercellular communication. In this review, we discuss the current understanding of the biological functions and therapeutic potential of MSC-derived ABs, including immunomodulation, tissue regeneration, regulation of inflammatory response, and drug delivery system.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233879
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3880: Dual-Specificity Protein Phosphatase 4 (DUSP4)
           Overexpression Improves Learning Behavior Selectively in Female 5xFAD
           Mice, and Reduces β-Amyloid Load in Males and Females

    • Authors: Allen L. Pan, Mickael Audrain, Emmy Sakakibara, Rajeev Joshi, Xiaodong Zhu, Qian Wang, Minghui Wang, Noam D. Beckmann, Eric E. Schadt, Sam Gandy, Bin Zhang, Michelle E. Ehrlich, Stephen R. Salton
      First page: 3880
      Abstract: Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF, is downregulated in postmortem Alzheimer’s disease (AD) brains. We investigated the roles that this VGF/DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12–18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233880
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3881: Novel Roles of Nanog in Cancer Cells and Their
           Extracellular Vesicles

    • Authors: Mikako Saito
      First page: 3881
      Abstract: The use of extracellular vesicle (EV)-based vaccines is a strategically promising way to prevent cancer metastasis. The effective roles of immune cell-derived EVs have been well understood in the literature. In the present paper, we focus on cancer cell-derived EVs to enforce, more thoroughly, the use of EV-based vaccines against unexpected malignant cells that might appear in poor prognostic patients. As a model of such a cancer cell with high malignancy, Nanog-overexpressing melanoma cell lines were developed. As expected, Nanog overexpression enhanced the metastatic potential of melanomas. Against our expectations, a fantastic finding was obtained that determined that EVs derived from Nanog-overexpressing melanomas exhibited a metastasis-suppressive effect. This is considered to be a novel role for Nanog in regulating the property of cancer cell-derived EVs. Stimulated by this result, the review of Nanog’s roles in various cancer cells and their EVs has been updated once again. Although there was no other case presenting a similar contribution by Nanog, only one case suggested that NANOG and SOX might be better prognosis markers in head and neck squamous cell carcinomas. This review clarifies the varieties of Nanog-dependent phenomena and the relevant signaling factors. The information summarized in this study is, thus, suggestive enough to generate novel ideas for the construction of an EV-based versatile vaccine platform against cancer metastasis.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233881
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3882: Cardiovascular, Pulmonary, and
           Neuropsychiatric Short- and Long-Term Complications of COVID-19

    • Authors: Małgorzata Kobusiak-Prokopowicz, Katarzyna Fułek, Michał Fułek, Konrad Kaaz, Andrzej Mysiak, Donata Kurpas, Jan Aleksander Beszłej, Anna Brzecka, Jerzy Leszek
      First page: 3882
      Abstract: Beginning with the various strategies of the SARS-CoV-2 virus to invade our bodies and manifest infection, and ending with the recent long COVID, we are witnessing the evolving course of the disease in addition to the pandemic. Given the partially controlled course of the COVID-19 pandemic, the greatest challenge currently lies in managing the short- and long-term complications of COVID-19. We have assembled current knowledge of the broad spectrum of cardiovascular, pulmonary, and neuropsychiatric sequelae following SARS-CoV-2 infection to understand how these clinical manifestations collectively lead to a severe form of the disease. The ultimate goal would be to better understand these complications and find ways to prevent clinical deterioration.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233882
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3883: Autophagy Induced by Toll-like Receptor
           Ligands Regulates Antigen Extraction and Presentation by B Cells

    • Authors: Jonathan Lagos, Sara Sagadiev, Jheimmy Diaz, Juan Pablo Bozo, Fanny Guzman, Caroline Stefani, Silvana Zanlungo, Mridu Acharya, Maria Isabel Yuseff
      First page: 3883
      Abstract: The engagement of B cells with surface-tethered antigens triggers the formation of an immune synapse (IS), where the local secretion of lysosomes can facilitate antigen uptake. Lysosomes intersect with other intracellular processes, such as Toll-like Receptor (TLR) signaling and autophagy coordinating immune responses. However, the crosstalk between these processes and antigen presentation remains unclear. Here, we show that TLR stimulation induces autophagy in B cells and decreases their capacity to extract and present immobilized antigens. We reveal that TLR stimulation restricts lysosome repositioning to the IS by triggering autophagy-dependent degradation of GEF-H1, a Rho GTP exchange factor required for stable lysosome recruitment at the synaptic membrane. GEF-H1 degradation is not observed in B cells that lack αV integrins and are deficient in TLR-induced autophagy. Accordingly, these cells show efficient antigen extraction in the presence of TLR stimulation, confirming the role of TLR-induced autophagy in limiting antigen extraction. Overall, our results suggest that resources associated with autophagy regulate TLR and BCR-dependent functions, which can finetune antigen uptake by B cells. This work helps to understand the mechanisms by which B cells are activated by surface-tethered antigens in contexts of subjacent inflammation before antigen recognition, such as sepsis.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233883
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3884: Comparison of the Immune Response in
           Vaccinated People Positive and Negative to SARS-CoV-2 Employing FTIR

    • Authors: Gustavo Jesus Vazquez-Zapien, Adriana Martinez-Cuazitl, Miguel Sanchez-Brito, Raul Jacobo Delgado-Macuil, Consuelo Atriano-Colorado, Francisco Garibay-Gonzalez, Virginia Sanchez-Monroy, Alberto Lopez-Reyes, Monica Maribel Mata-Miranda
      First page: 3884
      Abstract: Various immunopathological events characterize the systemic acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Moreover, it has been reported that coronavirus disease 2019 (COVID-19) vaccination and infection by SARS-CoV-2 induce humoral immunity mediated by B-cell-derived antibodies and cellular immunity mediated by T cells and memory B cells. Immunoglobulins, cytokines, and chemokines play an important role in shaping immunity in response to infection and vaccination. Furthermore, different vaccines have been developed to prevent COVID-19. Therefore, this research aimed to analyze and compare Fourier-transform infrared (FTIR) spectra of vaccinated people with a positive (V-COVID-19 group) or negative (V-Healthy group) real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) test, evaluating the immunoglobulin and cytokine content as an immunological response through FTIR spectroscopy. Most individuals that integrated the V-Healthy group (88.1%) were asymptomatic; on the contrary, only 28% of the V-COVID-19 group was asymptomatic. Likewise, 68% of the V-COVID-19 group had at least one coexisting illness. Regarding the immunological response analyzed through FTIR spectroscopy, the V-COVID-19 group showed a greater immunoglobulins G, A, and M (IgG, IgA, and IgM) content, as well as the analyzed cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-ɑ), and interleukins 1β, 6, and 10 (IL-1β, IL-6, and IL-10). Therefore, we can state that it was possible to detect biochemical changes through FTIR spectroscopy associated with COVID-19 immune response in vaccinated people.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233884
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3885: Protein Kinase D1 Signaling in Cancer Stem
           Cells with Epithelial-Mesenchymal Plasticity

    • Authors: Yichen Guo, Yinan Jiang, J. Bart Rose, Ganji Purnachandra Nagaraju, Renata Jaskula-Sztul, Anita B. Hjelmeland, Adam W. Beck, Herbert Chen, Bin Ren
      First page: 3885
      Abstract: Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233885
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3886: Cathelicidin-Related Antimicrobial Peptide
           Negatively Regulates Bacterial Endotoxin-Induced Glial Activation

    • Authors: Anup Bhusal, Youngpyo Nam, Donggun Seo, Won-Ha Lee, Kyoungho Suk
      First page: 3886
      Abstract: Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233886
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3887: Trifloroside Induces Bioactive Effects on
           Differentiation, Adhesion, Migration, and Mineralization in Pre-Osteoblast
           MC3T3E-1 Cells

    • Authors: Hyung-Mun Yun, Bomi Kim, Ji Eun Park, Kyung-Ran Park
      First page: 3887
      Abstract: Gentianae Scabrae Radix is used in traditional medicine and is known to possess bioactive compounds, including secoiridoid glycosides, flavonoids, lignans, and triterpenes. Trifloroside (TriFs) is a secoiridoid glycoside known for its antioxidant activity; however, its other effects have not been studied. In the present study, we investigated the biological effects of TriFs isolated from the roots of Gentianae Scabrae Radix using pre-osteoblast MC3T3E-1 cells. No cellular toxicity was observed with 1 mM TriFs, whereas 5–100 mM TriFs showed a gradual increase in cell viability. Alkaline phosphatase staining and microscopic observations revealed that 1–10 mM TriFs stimulated osteogenic activity during early osteoblast differentiation. Trifloroside also increased mineral apposition during osteoblast maturation. Biochemical analyses revealed that TriFs promoted nuclear RUNX2 expression and localization by stimulating the major osteogenic BMP2-Smad1/5/8-RUNX2 pathway. Trifloroside also increased p-GSK3b, β-catenin, p-JNK, and p-p38, but not Wnt3a, p-AKT, and p-ERK. Moreover, TriFs increased the MMP13 levels and promoted cell migration and adhesion. In contrast, TriFs-induced osteoblast differentiation and maturation had negligible effects on autophagy and necrosis. Our findings suggest that TriFs induces osteogenic effects through differentiation, adhesion, migration, and mineral apposition. Therefore, TriFs is suggested as a potential drug target in osteoblast-mediated bone diseases.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233887
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3888: Editing of a Novel Cd Uptake-Related Gene CUP1
           Contributes to Reducing Cd Accumulations in Arabidopsis thaliana and
           Brassica napus

    • Authors: Junyu Yao, Jiuyuan Bai, Sha Liu, Jingyan Fu, Ying Zhang, Tianshun Luo, Hongpei Ren, Rui Wang, Yun Zhao
      First page: 3888
      Abstract: Brassica napus is a Cd hyperaccumulator, which is a serious threat to food and fodder safety. However, no related studies on developing Cd-safe B. napus have been reported yet. Here, we screened out a novel Cd uptake-related gene, AtCUP1, from the major facilitator superfamily in Arabidopsis thaliana. The mutation of AtCUP1 decreased Cd accumulation, both in roots and shoots of A. thaliana. Furthermore, the disruption of the AtCUP1 gene by the CRISPR/Cas9 system significantly reduced Cd accumulation in A. thaliana. Interestingly, the disruption of the BnCUP1 gene, an orthologous gene of AtCUP1, by the CRISPR/Cas9 system also diminished Cd accumulation in both roots and shoots of B. napus based on the hydroponics assay. Furthermore, for the field experiment, the Cd accumulations of BnCUP1-edited lines were reduced by 52% in roots and 77% in shoots compared to that of wild-type (WT) lines, and the biomass and yield of BnCUP1-edited lines increased by 42% and 47% of that of WT, respectively. Noteworthily, agronomic characteristics of B. napus were not apparently affected by BnCUP1-editing. Thus, BnCUP1-edited lines are excellent non-transgenic germplasm resources for reducing Cd accumulation without a distinct compromise in yield, which could be applied to agricultural production in Cd-contaminated soils.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233888
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3889: Propranolol Modulates Cerebellar Circuit
           Activity and Reduces Tremor

    • Authors: Joy Zhou, Meike E. Van der Heijden, Luis E. Salazar Leon, Tao Lin, Lauren N. Miterko, Dominic J. Kizek, Ross M. Perez, Matea Pavešković, Amanda M. Brown, Roy V. Sillitoe
      First page: 3889
      Abstract: Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through β1 and β2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in β1 and β2 null mice or Car8wdl/wdl mice lacking β1 and β2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through β-adrenergic receptors and may contribute to tremor therapeutics.
      Citation: Cells
      PubDate: 2022-12-01
      DOI: 10.3390/cells11233889
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3890: The Interface of Tumour-Associated Macrophages
           with Dying Cancer Cells in Immuno-Oncology

    • Authors: Isaure Vanmeerbeek, Jannes Govaerts, Raquel S. Laureano, Jenny Sprooten, Stefan Naulaerts, Daniel M. Borras, Damya Laoui, Massimiliano Mazzone, Jo A. Van Ginderachter, Abhishek D. Garg
      First page: 3890
      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 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.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233890
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3891: Hypothalamic-Pituitary-Adrenal Hormones Impair
           Pig Fertilization and Preimplantation Embryo Development via Inducing
           Oviductal Epithelial Apoptosis: An In Vitro Study

    • Authors: Jin-Song An, Guo-Liang Wang, Dong-Ming Wang, Yong-Qing Yang, Jia-Shun Wu, Ying-Qi Zhao, Shuai Gong, Jing-He Tan
      First page: 3891
      Abstract: Previous studies show that stressful events after ovulation in sows significantly impaired the embryo cleavage with a significant elevation of blood cortisol. However, the effects of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol on fertilization and embryo development remain to be specified, and whether they damage pig embryos directly or indirectly is unclear. This study demonstrated that embryo development was unaffected when pig parthenotes were cultured with different concentrations of CRH/ACTH/cortisol. However, embryo development was significantly impaired when the embryos were cocultured with pig oviductal epithelial cells (OECs) in the presence of CRH/cortisol or cultured in medium that was conditioned with CRH/cortisol-pretreated OECs (CRH/cortisol-CM). Fertilization in CRH/cortisol-CM significantly increased the rates of polyspermy. CRH and cortisol induced apoptosis of OECs through FAS and TNFα signaling. The apoptotic OECs produced less growth factors but more FASL and TNFα, which induced apoptosis in embryos. Pig embryos were not sensitive to CRH because they expressed no CRH receptor but the CRH-binding protein, and they were tolerant to cortisol because they expressed more 11-beta hydroxysteroid dehydrogenase 2 (HSD11B2) than HSD11B1. When used at a stress-induced physiological concentration, while culture with either CRH or cortisol alone showed no effect, culture with both significantly increased apoptosis in OECs. In conclusion, CRH and cortisol impair pig fertilization and preimplantation embryo development indirectly by inducing OEC apoptosis via the activation of the FAS and TNFα systems. ACTH did not show any detrimental effect on pig embryos, nor OECs.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233891
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3892: Bone Marrow Mesenchymal Stromal/Stem
           Cell-Derived Extracellular Vesicles Promote Corneal Wound Repair by
           Regulating Inflammation and Angiogenesis

    • Authors: Gabriele Saccu, Valeria Menchise, Chiara Gai, Marina Bertolin, Stefano Ferrari, Cristina Giordano, Marta Manco, Walter Dastrù, Emanuela Tolosano, Benedetta Bussolati, Enzo Calautti, Giovanni Camussi, Fiorella Altruda, Sharmila Fagoonee
      First page: 3892
      Abstract: Severe corneal damage leads to complete vision loss, thereby affecting life quality and impinging heavily on the healthcare system. Current clinical approaches to manage corneal wounds suffer from severe drawbacks, thus requiring the development of alternative strategies. Of late, mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) have become a promising tool in the ophthalmic field. In the present study, we topically delivered bone-marrow-derived MSC-EVs (BMSC-EVs), embedded in methylcellulose, in a murine model of alkali-burn-induced corneal damage in order to evaluate their role in corneal repair through histological and molecular analyses, with the support of magnetic resonance imaging. Our data show that BMSC-EVs, used for the first time in this specific formulation on the damaged cornea, modulate cell death, inflammation and angiogenetic programs in the injured tissue, thus leading to a faster recovery of corneal damage. These results were confirmed on cadaveric donor-derived human corneal epithelial cells in vitro. Thus, BMSC-EVs modulate corneal repair dynamics and are promising as a new cell-free approach for intervening on burn wounds, especially in the avascularized region of the eye.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233892
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3893: Tumor Cell Derived Exosomal GOT1 Suppresses
           Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by
           Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression

    • Authors: Yao Guo, Taoyu Chen, Xueyi Liang, Shanmiao Gou, Jiongxin Xiong, Jing Cui, Tao Peng
      First page: 3893
      Abstract: Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233893
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3894: Pro- and Anti-Tumoral Factors Involved in
           Total Body Irradiation and Interleukin-2 Conditioning in Adoptive T Cell
           Therapy of Melanoma-Bearing Rag1 Knock-Out Mice

    • Authors: Seon-Hee Kim, Eun Mi Go, Dong Hoon Shin, Beom K. Choi, Chungyong Han
      First page: 3894
      Abstract: In adoptive T cell therapy (ACT), the transfer of tumor-specific T cells is paralleled by the conditioning regimen to increase therapeutic efficacy. Pre-conditioning depletes immune-suppressive cells and post-conditioning increases homeostatic signals to improve the persistence of administered T cells. Identifying the favorable immunological factors involved in a conditioning regimen is important to design effective strategies in ACT. Here, by using an ACT model of murine melanoma, we evaluate the effect of the total body irradiation (TBI) and interleukin-2 (IL-2) treatment combination. The use of a Rag1 knock-out strain, which lacks endogenous T cells, enables the identification of factors in a way that focuses more on transferred T cells. We demonstrate that the TBI/IL-2 combination has no additive effect in ACT, although each conditioning improves the therapeutic outcome. While the combination increases the frequency of transferred T cells in lymphoid and tumor tissues, the activation intensity of the cells is reduced compared to that of the sole TBI treatment. Notably, we show that in the presence of TBI, the IL-2 treatment reduces the frequency of intra-tumoral dendritic cells, which are crucial for T cell activation. The current study provides insights into the immunological events involved in the TBI/IL-2 combination in ACT.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233894
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3895: Impaired Autophagy Causes Severe Corneal

    • Authors: Kun Yi, Yuping Yang, Ye Yuan, Yingqian Xiang, Shanbi Zhou
      First page: 3895
      Abstract: Purpose: To investigate the role of macrophage autophagy in the process of corneal neovascularization (CNV). Methods: In vivo, mice CNV was induced by alkali injury and compared with rapamycin-treated alkaline burn mice. Western blot was used to determine the autophagic status of the macrophages. We quantified the levels of macrophage polarization markers (CD86, INOS, CD163, CD206) by RT-qPCR and measured inflammatory factors through ELISA (IL-6 and TNF-α) in the early phase after injury. In vitro, the human umbilical vein endothelial cells (HUVECs) were co-cultured with macrophage-conditioned medium (MCM) induced by the THP-1 cell line to simulate the neovascular microenvironment. The vascularization capacity of HUVECs was examined using the CCK-8 assay kit, tube formation assay, and scratch wound-healing assay. Results: In vivo, the mRNA expression of Beclin-1 and ATG5 was increased, together with the upregulation of M1 macrophage markers (CD86 and INOS) in corneas after early alkali injury. The area of CNV is effectively relieved in the rapamycin-treated mice. In vitro, upregulation of autophagy level by pretreatment with 3-methyladenine (3-MA) could increase the mRNA expression of the M1 markers. Macrophage-conditioned medium with impaired autophagy contains more IL-6 and TNF-α compared to the M1 macrophage-conditioned medium, promoting HUVEC proliferation, migration, and tube formation capacity. Enhancing the autophagy level with rapamycin (RAPA) could reverse this phenomenon. Conclusions: Impaired autophagy promoted macrophage polarization toward M1 type and increased the expression of IL-6 and TNF-α, which led to severe CNV. Using the autophagy activator (RAPA) could effectively alleviate CNV by promoting autophagy.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233895
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3896: The Dynamics of Cryptococcus neoformans Cell
           and Transcriptional Remodeling during Infection

    • Authors: Gustavo J. C. Freitas, Ludmila Gouveia-Eufrasio, Eluzia C. P. Emidio, Hellem C. S. Carneiro, Ludmila de Matos Baltazar, Marliete C. Costa, Susana Frases, Glauber R. de Sousa Araújo, Tatiane A. Paixão, Brunno G. Sossai, Melissa Caza, James W. Kronstad, Nalu T. A. Peres, Daniel A. Santos
      First page: 3896
      Abstract: The phenotypic plasticity of Cryptococcus neoformans is widely studied and demonstrated in vitro, but its influence on pathogenicity remains unclear. In this study, we investigated the dynamics of cryptococcal cell and transcriptional remodeling during pulmonary infection in a murine model. We showed that in Cryptococcus neoformans, cell size reduction (cell body ≤ 3 µm) is important for initial adaptation during infection. This change was associated with reproductive fitness and tissue invasion. Subsequently, the fungus develops mechanisms aimed at resistance to the host’s immune response, which is determinant for virulence. We investigated the transcriptional changes involved in this cellular remodeling and found an upregulation of transcripts related to ribosome biogenesis at the beginning (6 h) of infection and a later (10 days) upregulation of transcripts involved in the inositol pathway, energy production, and the proteasome. Consistent with a role for the proteasome, we found that its inhibition delayed cell remodeling during infection with the H99 strain. Altogether, these results further our understanding of the infection biology of C. neoformans and provide perspectives to support therapeutic and diagnostic targets for cryptococcosis.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233896
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3897: The Potential Role of R4 Regulators of G
           Protein Signaling (RGS) Proteins in Type 2 Diabetes Mellitus

    • Authors: Xiaohong Zhang, Hongyan Lv, Juan Mei, Bingyuan Ji, Shuhong Huang, Xuezhi Li
      First page: 3897
      Abstract: Type 2 diabetes mellitus (T2DM) is a complex and heterogeneous disease that primarily results from impaired insulin secretion or insulin resistance (IR). G protein-coupled receptors (GPCRs) are proposed as therapeutic targets for T2DM. GPCRs transduce signals via the Gα protein, playing an integral role in insulin secretion and IR. The regulators of G protein signaling (RGS) family proteins can bind to Gα proteins and function as GTPase-activating proteins (GAP) to accelerate GTP hydrolysis, thereby terminating Gα protein signaling. Thus, RGS proteins determine the size and duration of cellular responses to GPCR stimulation. RGSs are becoming popular targeting sites for modulating the signaling of GPCRs and related diseases. The R4 subfamily is the largest RGS family. This review will summarize the research progress on the mechanisms of R4 RGS subfamily proteins in insulin secretion and insulin resistance and analyze their potential value in the treatment of T2DM.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233897
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3898: Editorial (Preface) “Cells/Cells of the
           Cardiovascular System—Editorial Highlights 2020–2021: The Book

    • Authors: Kay-Dietrich Wagner
      First page: 3898
      Abstract: This introduction provides a preface to the section on “Cells of the Cardiovascular System” in the book entitled “Editor’s Choice Articles in 2020–2021” [...]
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233898
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3899: The Role of Oxytocin in Abnormal Brain
           Development: Effect on Glial Cells and Neuroinflammation

    • Authors: Marit Knoop, Marie-Laure Possovre, Alice Jacquens, Alexandre Charlet, Olivier Baud, Pascal Darbon
      First page: 3899
      Abstract: The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233899
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3900: MALDI Mass Spectrometry Imaging: A Potential
           Game-Changer in a Modern Microbiology

    • Authors: Maureen Feucherolles, Gilles Frache
      First page: 3900
      Abstract: Nowadays, matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is routinely implemented as the reference method for the swift and straightforward identification of microorganisms. However, this method is not flawless and there is a need to upgrade the current methodology in order to free the routine lab from incubation time and shift from a culture-dependent to an even faster independent culture system. Over the last two decades, mass spectrometry imaging (MSI) gained tremendous popularity in life sciences, including microbiology, due to its ability to simultaneously detect biomolecules, as well as their spatial distribution, in complex samples. Through this literature review, we summarize the latest applications of MALDI-MSI in microbiology. In addition, we discuss the challenges and avenues of exploration for applying MSI to solve current MALDI-TOF MS limits in routine and research laboratories.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233900
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3901: Mesoscopic Mapping of Visual Pathway in a
           Female 5XFAD Mouse Model of Alzheimer’s Disease

    • Authors: Yunkwon Nam, Sujin Kim, Jieun Kim, Hyang-Sook Hoe, Minho Moon
      First page: 3901
      Abstract: Amyloid-β (Aβ) deposition and Aβ-induced neurodegeneration appear in the retina and retinorecipient areas in the early stages of Alzheimer’s disease (AD). Although these Aβ-related changes in the retina cause damage to the visual functions, no studies have yet revealed the alterations in the visual pathways of AD. Therefore, we investigated the alterations of visual circuits in the AD mouse model using anterograde tracer cholera toxin β subunits (CTβ). Moreover, we investigated the Aβ accumulation in the retina and retinorecipient areas and the neuronal loss, and synaptic degeneration in retinorecipient areas by immunofluorescent staining of 4- and 12-month-old female 5XFAD transgenic mice. Our results demonstrated that Aβ accumulation and neurodegeneration occurred in the retina and retinorecipient regions of early and late stages of the 5XFAD mice. Retinal efferents to the suprachiasmatic nucleus and lateral geniculate nucleus were impaired in the early stage of AD. Moreover, retinal connections to the dorsal lateral geniculate nucleus and superior colliculus were degenerated in the late-stage of AD. These findings reveal the Aβ-related pathology induced visual circuit disturbances at the mesoscale level in both the early and late stages of AD and provide anatomical and functional insights into the visual circuitry of AD.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233901
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3902: Synapsin III Regulates Dopaminergic Neuron
           Development in Vertebrates

    • Authors: Gaia Faustini, Francesca Longhena, Alessia Muscò, Federica Bono, Edoardo Parrella, Luca La Via, Alessandro Barbon, Marina Pizzi, Franco Onofri, Fabio Benfenati, Cristina Missale, Maurizio Memo, Daniela Zizioli, Arianna Bellucci
      First page: 3902
      Abstract: Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233902
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3903: Dermal Telocytes: A Different Viewpoint of
           Skin Repairing and Regeneration

    • Authors: Catalin G. Manole, Mihaela Gherghiceanu, Laura Cristina Ceafalan, Mihail E. Hinescu
      First page: 3903
      Abstract: Fifteen years after their discovery, telocytes (TCs) are yet perceived as a new stromal cell type. Their presence was initially documented peri-digestively, and gradually throughout the interstitia of many (non-)cavitary mammalian, human, and avian organs, including skin. Each time, TCs proved to be involved in diverse spatial relations with elements of interstitial (ultra)structure (blood vessels, nerves, immune cells, etc.). To date, transmission electron microscopy (TEM) remained the single main microscopic technique able to correctly and certainly attest TCs by their well-acknowledged (ultra)structure. In skin, dermal TCs reiterate almost all (ultra)structural features ascribed to TCs in other locations, with apparent direct implications in skin physiology and/or pathology. TCs’ uneven distribution within skin, mainly located in stem cell niches, suggests involvement in either skin homeostasis or dermatological pathologies. On the other hand, different skin diseases involve different patterns of disruption of TCs’ structure and ultrastructure. TCs’ cellular cooperation with other interstitial elements, their immunological profile, and their changes during remission of diseases suggest their role(s) in tissue regeneration/repair processes. Thus, expanding the knowledge on dermal TCs could offer new insights into the natural skin capacity of self-repairing. Moreover, it would become attractive to consider that augmenting dermal TCs’ presence/density could become an attractive therapeutic alternative for treating various skin defects.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233903
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3904: Liposome-Mediated Gene Transfer in
           Differentiated HepaRG™ Cells: Expression of Liver Specific Functions
           and Application to the Cytochrome P450 2D6 Expression

    • Authors: Manuel Vlach, Hugo Coppens-Exandier, Agnès Jamin, Mathieu Berchel, Julien Scaviner, Christophe Chesné, Tristan Montier, Paul-Alain Jaffrès, Anne Corlu, Pascal Loyer
      First page: 3904
      Abstract: The goal of this study was to establish a procedure for gene delivery mediated by cationic liposomes in quiescent differentiated HepaRG™ human hepatoma cells. We first identified several cationic lipids promoting efficient gene transfer with low toxicity in actively dividing HepG2, HuH7, BC2 and progenitor HepaRG™ human hepatoma cells. The lipophosphoramidate Syn1-based nanovector, which allowed the highest transfection efficiencies of progenitor HepaRG™ cells, was next used to transfect differentiated HepaRG™ cells. Lipofection of these cells using Syn1-based liposome was poorly efficient most likely because the differentiated HepaRG™ cells are highly quiescent. Thus, we engineered the differentiated HepaRG™ Mitogenic medium supplement (ADD1001) that triggered robust proliferation of differentiated cells. Importantly, we characterized the phenotypical changes occurring during proliferation of differentiated HepaRG™ cells and demonstrated that mitogenic stimulation induced a partial and transient decrease in the expression levels of some liver specific functions followed by a fast recovery of the full differentiation status upon removal of the mitogens. Taking advantage of the proliferation of HepaRG™ cells, we defined lipofection conditions using Syn1-based liposomes allowing transient expression of the cytochrome P450 2D6, a phase I enzyme poorly expressed in HepaRG cells, which opens new means for drug metabolism studies in HepaRG™ cells.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233904
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3905: Genomewide m6A Mapping Uncovers Dynamic
           Changes in the m6A Epitranscriptome of Cisplatin-Treated Apoptotic HeLa

    • Authors: Azime Akçaöz Alasar, Özge Tüncel, Ayşe Bengisu Gelmez, Buket Sağlam, İpek Erdoğan Vatansever, Bünyamin Akgül
      First page: 3905
      Abstract: Cisplatin (CP), which is a conventional cancer chemotherapeutic drug, induces apoptosis by modulating a diverse array of gene regulatory mechanisms. However, cisplatin-mediated changes in the m6A methylome are unknown. We employed an m6A miCLIP-seq approach to investigate the effect of m6A methylation marks under cisplatin-mediated apoptotic conditions on HeLa cells. Our high-resolution approach revealed numerous m6A marks on 972 target mRNAs with an enrichment on 132 apoptotic mRNAs. We tracked the fate of differentially methylated candidate mRNAs under METTL3 knockdown and cisplatin treatment conditions. Polysome profile analyses revealed perturbations in the translational efficiency of PMAIP1 and PHLDA1 transcripts. Congruently, PMAIP1 amounts were dependent on METTL3. Additionally, cisplatin-mediated apoptosis was sensitized by METTL3 knockdown. These results suggest that apoptotic pathways are modulated by m6A methylation events and that the METTL3–PMAIP1 axis modulates cisplatin-mediated apoptosis in HeLa cells.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233905
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3906: The N-Terminal Part of the 1A Domain of Desmin
           Is a Hot Spot Region for Putative Pathogenic DES Mutations Affecting
           Filament Assembly

    • Authors: Andreas Brodehl, Stephanie Holler, Jan Gummert, Hendrik Milting
      First page: 3906
      Abstract: Desmin is the major intermediate filament protein of all three muscle cell types, and connects different cell organelles and multi-protein complexes such as the cardiac desmosomes. Several pathogenic mutations in the DES gene cause different skeletal and cardiac myopathies. However, the significance of the majority of DES missense variants is currently unknown, since functional data are lacking. To determine whether desmin missense mutations within the highly conserved 1A coil domain cause a filament assembly defect, we generated a set of variants with unknown significance and systematically analyzed the filament assembly using confocal microscopy in transfected SW-13, H9c2 cells and cardiomyocytes derived from induced pluripotent stem cells. We found that mutations in the N-terminal part of the 1A coil domain affect filament assembly, leading to cytoplasmic desmin aggregation. In contrast, mutant desmin in the C-terminal part of the 1A coil domain forms filamentous structures comparable to wild-type desmin. Our findings suggest that the N-terminal part of the 1A coil domain is a hot spot for pathogenic desmin mutations, which affect desmin filament assembly. This study may have relevance for the genetic counselling of patients carrying variants in the 1A coil domain of the DES gene.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233906
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3907: The Emerging Roles of Extracellular Chaperones
           in Complement Regulation

    • Authors: Nicholas J. Geraghty, Sandeep Satapathy, Mark R. Wilson
      First page: 3907
      Abstract: The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233907
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3908: A Mathematical Model of Estradiol Production
           from Ultrasound Data for Bovine Ovarian Follicles

    • Authors: Malgorzata J. McEvoy, Marion McAfee, John A. Hession, Leo Creedon
      First page: 3908
      Abstract: In this paper, we present a new way to assess the concentration of estradiol (E2) and Insulin Growth Factor-1 (IGF) based on the results from ultrasound scans combined with mathematical models. The IGF1 model is based on the progesterone (P4) concentration, which can be estimated with models calculating P4 level based on the size/volume of corpus luteum (CL) measured during ultrasound scans. At this moment little is known about the underlying reasons for double ovulation and silent heat occurrences. Both of these are linked to the level of IGF1: double ovulations are linked to higher IGF1 levels and and silent heat is linked to lower E2 to P4 ratio. These models can help to improve understanding of the related concentrations of E2 and IGF1. Currently, it is known that diet and genetic factors have an impact on ovulation rates and silent heat. In this study, we also examine the decline of the production of E2 in vivo by atretic follicles throughout the process of atresia. This is the first recorded quantitative description of this decline.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233908
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3909: Exploring the Characteristics of
           Monkeypox-Related Genes in Pan-Cancer

    • Authors: Yong Liao, Zhiping Liu, Weile Ye, Zunnan Huang, Jiaojiao Wang
      First page: 3909
      Abstract: Monkeypox, an infectious virus that is a member of the Poxviridae family, has raised great threats to humans. Compared to the known oncoviruses, the relationship between monkeypox and cancer still remains obscure. Hence, in this study, we analyzed the multi-omics data from the Cancer Genome Atlas (TCGA) database by using genomic and transcriptomic approaches to comprehensively assess the monkeypox-related genes (MRGs) in tumor samples from 33 types of cancers. Based on the results, the expression of MRGs was highly correlated with the immune infiltration and could be further utilized to predict survival in cancer patients. Furthermore, it was shown that tumorigenesis and patient survival were frequently associated with the genomic alterations of MRGs. Moreover, pathway analysis showed that MRGs participated in the regulation of apoptosis, cell cycle, Epithelial to Mesenchymal Transition (EMT), DNA damage, and hormone androgen receptor (AR), as well as RAS/MAPK and RTK signaling pathways. Besides, we also developed the prognostic features and consensus clustering clusters of MRGs in cancers. Lastly, by mining the cancer drug sensitivity genomics database, we further identified a series of candidate drugs that may target MRGs. Collectively, this study revealed genomic alterations and clinical features of MRGs, which may provide new hints to explore the potential molecular mechanisms between viruses and cancers as well as to provide new clinical guidance of cancer patients who also face the threats during the monkeypox epidemic.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233909
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3910: Genome-Wide Association Study Identifies
           CDKN1A as a Novel Locus Associated with Muscle Fiber Composition

    • Authors: Ekaterina A. Semenova, Hirofumi Zempo, Eri Miyamoto-Mikami, Hiroshi Kumagai, Andrey K. Larin, Rinat I. Sultanov, Konstantin A. Babalyan, Andrey V. Zhelankin, Takuro Tobina, Keisuke Shiose, Ryo Kakigi, Takamasa Tsuzuki, Noriko Ichinoseki-Sekine, Hiroyuki Kobayashi, Hisashi Naito, Jatin Burniston, Edward V. Generozov, Noriyuki Fuku, Ildus I. Ahmetov
      First page: 3910
      Abstract: Muscle fiber composition is associated with physical performance, with endurance athletes having a high proportion of slow-twitch muscle fibers compared to power athletes. Approximately 45% of muscle fiber composition is heritable, however, single nucleotide polymorphisms (SNP) underlying inter-individual differences in muscle fiber types remain largely unknown. Based on three whole genome SNP datasets, we have shown that the rs236448 A allele located near the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene was associated with an increased proportion of slow-twitch muscle fibers in Russian (n = 151; p = 0.039), Finnish (n = 287; p = 0.03), and Japanese (n = 207; p = 0.008) cohorts (meta-analysis: p = 7.9 × 10−5. Furthermore, the frequency of the rs236448 A allele was significantly higher in Russian (p = 0.045) and Japanese (p = 0.038) elite endurance athletes compared to ethnically matched power athletes. On the contrary, the C allele was associated with a greater proportion of fast-twitch muscle fibers and a predisposition to power sports. CDKN1A participates in cell cycle regulation and is suppressed by the miR-208b, which has a prominent role in the activation of the slow myofiber gene program. Bioinformatic analysis revealed that the rs236448 C allele was associated with increased CDKN1A expression in whole blood (p = 8.5 × 10−15) and with greater appendicular lean mass (p = 1.2 × 10−5), whereas the A allele was associated with longer durations of exercise (p = 0.044) reported amongst the UK Biobank cohort. Furthermore, the expression of CDKN1A increased in response to strength (p < 0.0001) or sprint (p = 0.00035) training. Accordingly, we found that CDKN1A expression is significantly (p = 0.002) higher in the m. vastus lateralis of strength athletes compared to endurance athletes and is positively correlated with the percentage of fast-twitch muscle fibers (p = 0.018). In conclusion, our data suggest that the CDKN1A rs236448 SNP may be implicated in the determination of muscle fiber composition and may affect athletic performance.
      Citation: Cells
      PubDate: 2022-12-02
      DOI: 10.3390/cells11233910
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3911: Reduced MHC Class I and II Expression in
           HPV−Negative vs. HPV−Positive Cervical Cancers

    • Authors: Andris M. Evans, Mikhail Salnikov, Tanner M. Tessier, Joe S. Mymryk
      First page: 3911
      Abstract: Cervical cancer (CC) is the second most common cancer in women worldwide and the fourth leading cause of cancer-associated death in women. Although human papillomavirus (HPV) infection is associated with nearly all CC, it has recently become clear that HPV−negative (HPV−) CC represents a distinct disease phenotype with increased mortality. HPV−positive (HPV+) and HPV− CC demonstrate different molecular pathology, prognosis, and response to treatment. Furthermore, CC caused by HPV α9 types (HPV16-like) often have better outcomes than those caused by HPV α7 types (HPV18-like). This study systematically and comprehensively compared the expression of genes involved in major histocompatibility complex (MHC) class I and II presentation within CC caused by HPV α9 types, HPV α7 types, and HPV− CC. We observed increased expression of MHC class I and II classical and non-classical genes in HPV+ CC and overall higher expression of genes involved in their antigen loading and presentation apparatus as well as transcriptional regulation. Increased expression of MHC I-related genes differs from previous studies using cell culture models. These findings identify crucial differences between antigen presentation within the tumor immune microenvironments of HPV+ and HPV− CC, as well as modest differences between HPV α9 and α7 CC. These differences may contribute to the altered patient outcomes and responses to immunotherapy observed between these distinct cancers.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233911
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3912: Hematopoietic Cell Transplantation for
           Systemic Sclerosis—A Review

    • Authors: Daniel Levin, Mohammed S. Osman, Caylib Durand, Hyein Kim, Iman Hemmati, Kareem Jamani, Jonathan G. Howlett, Kerri A. Johannson, Jason Weatherald, Matthew Woo, Jason Lee, Jan Storek
      First page: 3912
      Abstract: Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233912
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3913: Signaling Pathways of Podocyte Injury in
           Diabetic Kidney Disease and the Effect of Sodium-Glucose Cotransporter 2

    • Authors: Xiutian Chen, Jiali Wang, Yongda Lin, Yiping Liu, Tianbiao Zhou
      First page: 3913
      Abstract: Diabetic kidney disease (DKD) is one of the most important comorbidities for patients with diabetes, and its incidence has exceeded one tenth, with an increasing trend. Studies have shown that diabetes is associated with a decrease in the number of podocytes. Diabetes can induce apoptosis of podocytes through several apoptotic pathways or induce autophagy of podocytes through related pathways. At the same time, hyperglycemia can also directly lead to apoptosis of podocytes, and the related inflammatory reactions are all harmful to podocytes. Podocyte damage is often accompanied by the production of proteinuria and the progression of DKD. As a new therapeutic agent for diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to be effective in the treatment of diabetes and the improvement of terminal outcomes in many rodent experiments and clinical studies. At the same time, SGLT2i can also play a protective role in diabetes-induced podocyte injury by improving the expression of nephrotic protein defects and inhibiting podocyte cytoskeletal remodeling. Some studies have also shown that SGLT2i can play a role in inhibiting the apoptosis and autophagy of cells. However, there is no relevant study that clearly indicates whether SGLT2i can also play a role in the above pathways in podocytes. This review mainly summarizes the damage to podocyte structure and function in DKD patients and related signaling pathways, as well as the possible protective mechanism of SGLT2i on podocyte function.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233913
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3914: Advances in Cellular Reprogramming-Based
           Approaches for Heart Regenerative Repair

    • Authors: Xingyu He, Jialiang Liang, Christian Paul, Wei Huang, Suchandrima Dutta, Yigang Wang
      First page: 3914
      Abstract: Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233914
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3915: Deciphering Transcriptional Networks during
           Human Cardiac Development

    • Authors: Robin Canac, Bastien Cimarosti, Aurore Girardeau, Virginie Forest, Pierre Olchesqui, Jeremie Poschmann, Richard Redon, Patricia Lemarchand, Nathalie Gaborit, Guillaume Lamirault
      First page: 3915
      Abstract: Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves. We then identified a regulatory network of more than 23,000 activation and inhibition links between 216 TFs. Within this network, we observed previously unknown inferred transcriptional activations linking IRX3 and IRX5 TFs to three master cardiac TFs: GATA4, NKX2-5 and TBX5. Luciferase and co-immunoprecipitation assays demonstrated that these five TFs could (1) activate each other’s expression; (2) interact physically as multiprotein complexes; and (3) together, finely regulate the expression of SCN5A, encoding the major cardiac sodium channel. Altogether, these results unveiled thousands of interactions between TFs, generating multiple robust hypotheses governing human cardiac development.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233915
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3916: Targeting mGlu1 Receptors in the Treatment of
           Motor and Cognitive Dysfunctions in Mice Modeling Type 1 Spinocerebellar

    • Authors: Francesca Liberatore, Nico Antenucci, Daniel Tortolani, Giada Mascio, Federico Fanti, Manuel Sergi, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Mauro Maccarrone, Serena Notartomaso
      First page: 3916
      Abstract: Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs. Here, we report that otherwise healthy, 8-week-old SCA1 mice showed a defect in spatial learning and memory associated with reduced protein levels of mGlu1α receptors, the GluN2B subunit of NMDA receptors, and cannabinoid CB1 receptors in the hippocampus. Systemic treatment with Ro0711401 (10 mg/kg, s.c.) partially corrected the learning deficit in the Morris water maze and restored memory retention in the SCA1 mice model. This treatment also enhanced hippocampal levels of the endocannabinoid, anandamide, without changing the levels of 2-arachidonylglycerol. These findings suggest that mGlu1 receptor PAMs may be beneficial in the treatment of motor and nonmotor signs associated with SCA1 and encourage further studies in animal models of SCA1 and other types of SCAs.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233916
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3917: CHRDL1 Regulates Stemness in Glioma Stem-like

    • Authors: Inka Berglar, Stephanie Hehlgans, Andrej Wehle, Caterina Roth, Christel Herold-Mende, Franz Rödel, Donat Kögel, Benedikt Linder
      First page: 3917
      Abstract: Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233917
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3918: Nucleophagic Degradation of Progerin
           Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to
           SIRT1-Mediated Deacetylation of Nuclear LC3

    • Authors: Yangqiu Bai, Jinying Liu, Xiaoke Jiang, Xiuling Li, Bingyong Zhang, Xiaoying Luo
      First page: 3918
      Abstract: Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis . Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about the role of nucleophagy in LSEC defenestration. Herein, we aim to dissect the underlying mechanism of progerin and nucleophagy in LSEC phenotype. We found an abnormal accumulation of progerin and a loss of SIRT1 in the nucleus of intrahepatic cells in human fibrotic liver tissue. In vivo, nuclear progerin abnormally accumulated in defenestrated LSECs, along with a depletion of SIRT1 and Cav-1 during liver fibrogenesis, whereas these effects were reversed by the overexpression of SIRT1 with the adenovirus vector. In vitro, H2O2 induced the excessive accumulation of progeirn, with the depletion of Lamin B1 and Cav-1 to aggravate LSEC defenestration. NAC and mito-TEMPO, classical antioxidants, inhibited NOX2- and NOX4-dependent oxidative stress to improve the depletion of Lamin B1 and Cav-1 and promoted progerin-related nucleophagy, leading to a reverse in H2O2-induced LSEC defenestration. However, rapamycin aggravated the H2O2-induced depletion of Lamin B1 and Cav-1 due to excessive autophagy, despite promoting progerin nucleophagic degradation. In addition, overexpressing SIRT1 with the adenovirus vector inhibited oxidative stress to rescue the production of Lamin B1 and Cav-1. Moreover, the SIRT1-mediated deacetylation of nuclear LC3 promoted progerin nucleophagic degradation and subsequently inhibited the degradation of Lamin B1 and Cav-1, as well as improved F-actin remodeling, contributing to maintaining LSEC fenestrae. Hence, our findings indicate a new strategy for reversing LSEC defenestration by promoting progerin clearance via the SIRT1-mediated deacetylation of nuclear LC3.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233918
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3919: Systematic Methods for Isolating High Purity
           Nuclei from Ten Important Plants for Omics Interrogation

    • Authors: Ming-Chao Yang, Zi-Chen Wu, Liang-Liang Huang, Farhat Abbas, Hui-Cong Wang
      First page: 3919
      Abstract: Recent advances in developmental biology have been made possible by using multi-omic studies at single cell resolution. However, progress in plants has been slowed, owing to the tremendous difficulty in protoplast isolation from most plant tissues and/or oversize protoplasts during flow cytometry purification. Surprisingly, rapid innovations in nucleus research have shed light on plant studies in single cell resolution, which necessitates high quality and efficient nucleus isolation. Herein, we present efficient nuclei isolation protocols from the leaves of ten important plants including Arabidopsis, rice, maize, tomato, soybean, banana, grape, citrus, apple, and litchi. We provide a detailed procedure for nucleus isolation, flow cytometry purification, and absolute nucleus number quantification. The nucleus isolation buffer formula of the ten plants tested was optimized, and the results indicated a high nuclei yield. Microscope observations revealed high purity after flow cytometry sorting, and the DNA and RNA quality extract from isolated nuclei were monitored by using the nuclei in cell division cycle and single nucleus RNA sequencing (snRNA-seq) studies, with detailed procedures provided. The findings indicated that nucleus yield and quality meet the requirements of snRNA-seq, cell division cycle, and likely other omic studies. The protocol outlined here makes it feasible to perform plant omic studies at single cell resolution.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233919
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3920: Low WIP1 Expression Accelerates Ovarian Aging
           by Promoting Follicular Atresia and Primordial Follicle Activation

    • Authors: Su Zhou, Yueyue Xi, Yingying Chen, Fangfang Fu, Wei Yan, Milu Li, Yaling Wu, Aiyue Luo, Ya Li, Shixuan Wang
      First page: 3920
      Abstract: Our previous study demonstrated that ovarian wild-type P53-induced phosphatase 1 (WIP1) expression decreased with age. We hypothesized that WIP1 activity was related to ovarian aging. The role of WIP1 in regulating ovarian aging and its mechanisms remain to be elucidated. Adult female mice with or without WIP1 inhibitor (GSK2830371) treatment were divided into three groups (Veh, GSK-7.5, GSK-15) to evaluate the effect of WIP1 on ovarian endocrine and reproductive function and the ovarian reserve. In vitro follicle culture and primary granulosa cell culture were applied to explore the mechanisms of WIP1 in regulating follicular development. This study revealed that WIP1 expression in atretic follicle granulosa cells is significantly lower than that in healthy follicles. Inhibiting WIP1 phosphatase activity in mice induced irregular estrous cycles, caused fertility declines, and decreased the ovarian reserve through triggering excessive follicular atresia and primordial follicle activation. Primordial follicle depletion was accelerated via PI3K-AKT-rpS6 signaling pathway activation. In vitro follicle culture experiments revealed that inhibiting WIP1 activity impaired follicular development and oocyte quality. In vitro granulosa cell experiments further indicated that downregulating WIP1 expression promoted granulosa cell death via WIP1-p53-BAX signaling pathway-mediated apoptosis. These findings suggest that appropriate WIP1 expression is essential for healthy follicular development, and decreased WIP1 expression accelerates ovarian aging by promoting follicular atresia and primordial follicle activation.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233920
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3921: Enterotoxin Gene Cluster and selX Are
           Associated with Atopic Dermatitis Severity—A Cross-Sectional
           Molecular Study of Staphylococcus aureus Superantigens

    • Authors: Leszek Blicharz, Maciej Żochowski, Ksenia Szymanek-Majchrzak, Joanna Czuwara, Mohamad Goldust, Krzysztof Skowroński, Grażyna Młynarczyk, Małgorzata Olszewska, Zbigniew Samochocki, Lidia Rudnicka
      First page: 3921
      Abstract: Staphylococcus aureus superantigens (SAgs) have been reported to aggravate atopic dermatitis. However, comprehensive analyses of these molecules in multiple microniches are lacking. The present study involved 50 adult patients with active atopic dermatitis. S. aureus was isolated from the lesional skin, nonlesional skin, and anterior nares. Multiplex-PCR was performed to identify genes encoding (1) selX (core genome); (2) seg, selI, selM, selN, selO, selU (enterotoxin gene cluster, EGC); and (3) sea, seb, sec, sed, see, tstH (classic SAgs encoded on other mobile genetic elements). The results were correlated to clinical parameters of the study group. selx and EGC were the most prevalent in all microniches. The number of SAg-encoding genes correlated between the anterior nares and nonlesional skin, and between the nonlesional and lesional skin. On lesional skin, the total number of SAg genes correlated with disease severity (total and objective SCORAD, intensity, erythema, edema/papulation, lichenification and dryness). Linear regression revealed that AD severity was predicted only by selx and EGC. This study revealed that selX and EGC are associated with atopic dermatitis severity. Anterior nares and nonlesional skin could be reservoirs of SAg-positive S. aureus. Restoring the physiological microbiome could reduce the SAg burden and alleviate syndromes of atopic dermatitis.
      Citation: Cells
      PubDate: 2022-12-03
      DOI: 10.3390/cells11233921
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3922: Ectopic Tumor VCAM-1 Expression in Cancer
           Metastasis and Therapy Resistance

    • Authors: Kristen A. VanHeyst, Sung Hee Choi, Daniel T. Kingsley, Alex Y. Huang
      First page: 3922
      Abstract: Vascular Cell Adhesion Molecule-1 (VCAM-1; CD106) is a membrane protein that contributes critical physiologic functional roles in cellular immune response, including leukocyte extravasation in inflamed and infected tissues. Expressed as a cell membrane protein, VCAM-1 can also be cleaved from the cell surface into a soluble form (sVCAM-1). The integrin α4β1 (VLA-4) was identified as the first major ligand for VCAM-1. Ongoing studies suggest that, in addition to mediating physiologic immune functions, VCAM-1/VLA-4 signaling plays an increasingly vital role in the metastatic progression of various tumors. Additionally, elevated concentrations of sVCAM-1 have been found in the peripheral blood of patients with cancer, suggesting the tumor microenvironment (TME) as the source of sVCAM-1. Furthermore, over-expression of VLA-4 was linked to tumor progression in various malignancies when VCAM-1 was also up-regulated. This review explores the functional role of VCAM-1 expression in cancer metastasis and therapy resistance, and the potential for the disruption of VCAM-1/VLA-4 signaling as a novel immunotherapeutic approach in cancer, including osteosarcoma, which disproportionately affects the pediatric, adolescent and young adult population, as an unmet medical need.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233922
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3923: Micro-RNAs Shuttled by Extracellular Vesicles
           Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological
           Activation and Support Neuroprotection in In-Vitro Models of ALS

    • Authors: Francesca Provenzano, Sophie Nyberg, Debora Giunti, Carola Torazza, Benedetta Parodi, Tiziana Bonifacino, Cesare Usai, Nicole Kerlero de Kerlero de Rosbo, Marco Milanese, Antonio Uccelli, Pamela J. Shaw, Laura Ferraiuolo, Giambattista Bonanno
      First page: 3923
      Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes’ neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1G93A astrocytes with single miRNA mimics reduced astrocytes’ activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes’ reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233923
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3924: Unbalanced Glutamine Partitioning between CD8T
           Cells and Cancer Cells Accompanied by Immune Cell Dysfunction in
           Hepatocellular Carcinoma

    • Authors: Jianfei Chen, Rui Wang, Zhongliang Liu, Jun Fan, Shenglu Liu, Shunde Tan, Xinkai Li, Liuyao Fan, Bo Li, Xiaoli Yang
      First page: 3924
      Abstract: Glutamine metabolism is critical both for the proliferation of cancer cells and the activation of CD8T cells to kill cancer cells. We aim to explore the relationship between the glutamine metabolism of CD8T cells and cancer cells and tumor immunity in the tumor microenvironment. In a TCGA cohort, we found that patients with high scores of glutamine-metabolism-related genes showed poor prognoses, and that a high score of glutamine-metabolism-related genes was an independent risk factor for HCC patients. In single-cell RNA-seq data, we found that, in some patients, the glutamine metabolism gene scores of tumor cells were significantly higher than those of CD8T cells, while decreased ratios of CD8-Tef-GZMA and suppressed tumor-killing activity of CD8-Tef-APOC2 were observed. A further genetic dynamics pseudotime analysis suggested that immune remodeling of these two subpopulations was accompanied by metabolic reprogramming. CD8-Tef-APOC2 in the dominant group tended to metabolize exogenous lipids, while the metabolic program of CD8-Tef-GZMA in the nondominant group was characterized by amino acid and endogenous lipid synthesis. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the proliferation of CD8T cells and improved the efficacy of PD-1 blockers. We proposed a new tool to quantify the glutamine partitioning between tumor cells and CD8T cells, through which the unique immune microenvironment could be identified at the transcriptome level. Furthermore, the simultaneous destruction of the glutamine metabolism in tumor cells and CD8T cells facilitated the enrichment of tumor-infiltrating CD8T cells and enhanced the efficacy of immunotherapy.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233924
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3925: Modeling the Endothelial Glycocalyx Layer in
           the Human Conventional Aqueous Outflow Pathway

    • Authors: Alireza Karimi, Mahdi Halabian, Reza Razaghi, J. Crawford Downs, Mary J. Kelley, Ted S. Acott
      First page: 3925
      Abstract: A layer of proteoglycans and glycoproteins known as glycocalyx covers the surface of the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and Schlemm’s canal (SC) inner wall of the conventional aqueous outflow pathway in the eye. This has been shown to play a role in the mechanotransduction of fluid shear stress and in the regulation of the outflow resistance. The outflow resistance in the conventional outflow pathway is the main determinant of the intraocular pressure (IOP) through an active, two-way, fluid–structure interaction coupling between the outflow tissues and aqueous humor. A 3D microstructural finite element (FE) model of a healthy human eye TM/JCT/SC complex with interspersed aqueous humor was constructed. A very thin charged double layer that represents the endothelial glycocalyx layer covered the surface of the elastic outflow tissues. The aqueous humor was modeled as electroosmotic flow that is charged when it is in contact with the outflow tissues. The electrical–fluid–structure interaction (EFSI) method was used to couple the charged double layer (glycocalyx), fluid (aqueous humor), and solid (outflow tissues). When the IOP was elevated to 15 mmHg, the maximum aqueous humor velocity in the EFSI model was decreased by 2.35 mm/s (9%) compared to the fluid–structure interaction (FSI) model. The charge or electricity in the living human conventional outflow pathway generated by the charged endothelial glycocalyx layer plays a minor biomechanical role in the resultant stresses and strains as well as the hydrodynamics of the aqueous humor.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233925
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3926: Oxidative Stress and Extracellular Matrix
           Remodeling Are Signature Pathways of Extracellular Vesicles Released upon
           Morphine Exposure on Human Brain Microvascular Endothelial Cells

    • Authors: Tatjana Vujić, Domitille Schvartz, Izadora Liranço Furlani, Isabel Meister, Víctor González-Ruiz, Serge Rudaz, Jean-Charles Sanchez
      First page: 3926
      Abstract: Morphine, a commonly used antinociceptive drug in hospitals, is known to cross the blood-brain barrier (BBB) by first passing through brain endothelial cells. Despite its pain-relieving effect, morphine also has detrimental effects, such as the potential induction of redox imbalance in the brain. However, there is still insufficient evidence of these effects on the brain, particularly on the brain endothelial cells and the extracellular vesicles that they naturally release. Indeed, extracellular vesicles (EVs) are nanosized bioparticles produced by almost all cell types and are currently thought to reflect the physiological state of their parent cells. These vesicles have emerged as a promising source of biomarkers by indicating the functional or dysfunctional state of their parent cells and, thus, allowing a better understanding of the biological processes involved in an adverse state. However, there is very little information on the morphine effect on human brain microvascular endothelial cells (HBMECs), and even less on their released EVs. Therefore, the current study aimed at unraveling the detrimental mechanisms of morphine exposure (at 1, 10, 25, 50 and 100 µM) for 24 h on human brain microvascular endothelial cells as well as on their associated EVs. Isolation of EVs was carried out using an affinity-based method. Several orthogonal techniques (NTA, western blotting and proteomics analysis) were used to validate the EVs enrichment, quality and concentration. Data-independent mass spectrometry (DIA-MS)-based proteomics was applied in order to analyze the proteome modulations induced by morphine on HBMECs and EVs. We were able to quantify almost 5500 proteins in HBMECs and 1500 proteins in EVs, of which 256 and 148, respectively, were found to be differentially expressed in at least one condition. Pathway enrichment analysis revealed that the “cell adhesion and extracellular matrix remodeling” process and the “HIF1 pathway”, a pathway related to oxidative stress responses, were significantly modulated upon morphine exposure in HBMECs and EVs. Altogether, the combination of proteomics and bioinformatics findings highlighted shared pathways between HBMECs exposed to morphine and their released EVs. These results put forward molecular signatures of morphine-induced toxicity in HBMECs that were also carried by EVs. Therefore, EVs could potentially be regarded as a useful tool to investigate brain endothelial cells dysfunction, and to a different extent, the BBB dysfunction in patient circulation using these “signature pathways”.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233926
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3927: Nrf2 Deficiency Exacerbated CLP-Induced
           Pulmonary Injury and Inflammation through Autophagy- and
           NF-κB/PPARγ-Mediated Macrophage Polarization

    • Authors: Jing Luo, Jin Wang, Jing Zhang, Aming Sang, Xujun Ye, Zhenshun Cheng, Xinyi Li
      First page: 3927
      Abstract: The balance between M1 and M2 macrophage polarization is involved in the regulation of pulmonary inflammation. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as Nrf2), a nuclear transcription factor, is reported to play protective roles in acute lung injury (ALI) and inflammation, and increasing evidence indicates that the protective effects of Nrf2 are closely related to autophagy. This study aimed to explore whether Nrf2 is involved in sepsis-induced acute pulmonary injury and inflammation and in the role of macrophage polarization in the process. In the present study, sepsis patients, an Nrf2 knockout mouse that underwent cecal ligation and puncture (CLP), and lipopolysaccharide (LPS)-treated macrophage cell lines were employed to investigate the potential functions of Nrf2 in sepsis-induced lung injury and the underlying mechanisms. Clinical studies showed that the NRF2 mRNA level was inversely correlated with pulmonary inflammation and disease severity in patients with sepsis. Analyses in a CLP-treated Nrf2 knockout mouse model indicated that an Nrf2 deficiency promoted a CLP-induced increase in M1 macrophage polarization and apoptosis and inhibited CLP-induced upregulation of the autophagy level in lung tissues. Experiments in RAW264.7 cells revealed that Nrf2 overexpression inhibited M1 macrophage polarization but promoted M2 macrophage polarization by improving the autophagy, and Nrf2 overexpression promoted PPARγ but inhibited NF-κB nuclear translocation. In conclusion, these results indicate that Nrf2 plays a protective role in sepsis-induced pulmonary injury and inflammation through the regulation of autophagy- and NF-κB/PPARγ-mediated macrophage polarization.
      Citation: Cells
      PubDate: 2022-12-04
      DOI: 10.3390/cells11233927
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3928: CRISPR/Cas Genome Editing Technologies for
           Plant Improvement against Biotic and Abiotic Stresses: Advances,
           Limitations, and Future Perspectives

    • Authors: Yaxin Wang, Naeem Zafar, Qurban Ali, Hakim Manghwar, Guanying Wang, Lu Yu, Xiao Ding, Fang Ding, Ni Hong, Guoping Wang, Shuangxia Jin
      First page: 3928
      Abstract: Crossbreeding, mutation breeding, and traditional transgenic breeding take much time to improve desirable characters/traits. CRISPR/Cas-mediated genome editing (GE) is a game-changing tool that can create variation in desired traits, such as biotic and abiotic resistance, increase quality and yield in less time with easy applications, high efficiency, and low cost in producing the targeted edits for rapid improvement of crop plants. Plant pathogens and the severe environment cause considerable crop losses worldwide. GE approaches have emerged and opened new doors for breeding multiple-resistance crop varieties. Here, we have summarized recent advances in CRISPR/Cas-mediated GE for resistance against biotic and abiotic stresses in a crop molecular breeding program that includes the modification and improvement of genes response to biotic stresses induced by fungus, virus, and bacterial pathogens. We also discussed in depth the application of CRISPR/Cas for abiotic stresses (herbicide, drought, heat, and cold) in plants. In addition, we discussed the limitations and future challenges faced by breeders using GE tools for crop improvement and suggested directions for future improvements in GE for agricultural applications, providing novel ideas to create super cultivars with broad resistance to biotic and abiotic stress.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233928
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3929: FGFR Inhibitors in Cholangiocarcinoma—A
           Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next
           in Targeting This Axis'

    • Authors: Paulina Chmiel, Katarzyna Gęca, Karol Rawicz-Pruszyński, Wojciech P. Polkowski, Magdalena Skórzewska
      First page: 3929
      Abstract: Cholangiocarcinomas (CCAs) are rare but aggressive tumours with poor diagnosis and limited treatment options. Molecular targeted therapies became a promising proposal for patients after progression under first-line chemical treatment. In light of an escalating prevalence of CCA, it is crucial to fully comprehend its pathophysiology, aetiology, and possible targets in therapy. Such knowledge would play a pivotal role in searching for new therapeutic approaches concerning diseases’ symptoms and their underlying causes. Growing evidence showed that fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathway dysregulation is involved in a variety of processes during embryonic development and homeostasis as well as tumorigenesis. CCA is known for its close correlation with the FGF/FGFR pathway and targeting this axis has been proposed in treatment guidelines. Bearing in mind the significance of molecular targeted therapies in different neoplasms, it seems most reasonable to move towards intensive research and testing on these in the case of CCA. However, there is still a need for more data covering this topic. Although positive results of many pre-clinical and clinical studies are discussed in this review, many difficulties lie ahead. Furthermore, this review presents up-to-date literature regarding the outcomes of the latest clinical data and discussion over future directions of FGFR-directed therapies in patients with CCA.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233929
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3930: An Altered Skin and Gut Microbiota Are
           Involved in the Modulation of Itch in Atopic Dermatitis

    • Authors: Catharina Sagita Moniaga, Mitsutoshi Tominaga, Kenji Takamori
      First page: 3930
      Abstract: Skin and gut microbiota play an important role in the pathogenesis of atopic dermatitis (AD). An alteration of the microbiota diversity modulates the development and course of AD, e.g., decreased microbiome diversity correlates with disease severity, particularly in lesional skin of AD. Itch is a hallmark of AD with unsatisfying treatment until now. Recent evidence suggests a possible role of microbiota in altering itch in AD through gut–skin–brain interactions. The microbial metabolites, proinflammatory cytokines, and impaired immune response lead to a modulation of histamine-independent itch, disruption of epidermal barrier, and central sensitization of itch mechanisms. The positive impact of probiotics in alleviating itch in AD supports this hypothesis, which may lead to novel strategies for managing itchy skin in AD patients. This review summarizes the emerging findings on the correlation between an altered microbiota and gut–skin–brain axis in AD, especially in modulating itchy skin.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233930
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3931: The Centrosome: Conclusions and Perspectives

    • Authors: Rustem E. Uzbekov, Tomer Avidor-Reiss
      First page: 3931
      Abstract: The centrosome consists of two centrioles surrounded by pericentriolar material [...]
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233931
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3932: PARP1 Activation Controls Stress Granule
           Assembly After Oxidative Stress and DNA Damage

    • Authors: Singatulina, Sukhanova, Desforges, Joshi, Pastré, Lavrik
      First page: 3932
      Abstract: DNA damage causes PARP1 activation in the nucleus to set up the machinery responsible for the DNA damage response. Here, we report that, in contrast to cytoplasmic PARPs, the synthesis of poly(ADP-ribose) by PARP1 opposes the formation of cytoplasmic mRNA-rich granules after arsenite exposure by reducing polysome dissociation. However, when mRNA-rich granules are pre-formed, whether in the cytoplasm or nucleus, PARP1 activation positively regulates their assembly, though without additional recruitment of poly(ADP-ribose) in stress granules. In addition, PARP1 promotes the formation of TDP-43- and FUS-rich granules in the cytoplasm, two RNA-binding proteins which form neuronal cytoplasmic inclusions observed in certain neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Together, the results therefore reveal a dual role of PARP1 activation which, on the one hand, prevents the early stage of stress granule assembly and, on the other hand, enables the persistence of cytoplasmic mRNA-rich granules in cells which may be detrimental in aging neurons.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233932
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3933: Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a
           Relevant Strategy for the Treatment of Paediatric Medulloblastomas

    • Authors: Manon Penco-Campillo, Clément Molina, Patricia Piris, Nouha Soufi, Manon Carré, Marina Pagnuzzi-Boncompagni, Vincent Picco, Maeva Dufies, Cyril Ronco, Rachid Benhida, Sonia Martial, Gilles Pagès
      First page: 3933
      Abstract: Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients’ quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood–brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233933
      Issue No: Vol. 11, No. 23 (2022)
  • Cells, Vol. 11, Pages 3934: Wnt Signaling in the Development of Bone

    • Authors: Noa Ben-Ghedalia-Peled, Razi Vago
      First page: 3934
      Abstract: Wnt signaling occurs through evolutionarily conserved pathways that affect cellular proliferation and fate decisions during development and tissue maintenance. Alterations in these highly regulated pathways, however, play pivotal roles in various malignancies, promoting cancer initiation, growth and metastasis and the development of drug resistance. The ability of cancer cells to metastasize is the primary cause of cancer mortality. Bone is one of the most frequent sites of metastases that generally arise from breast, prostate, lung, melanoma or kidney cancer. Upon their arrival to the bone, cancer cells can enter a long-term dormancy period, from which they can be reactivated, but can rarely be cured. The activation of Wnt signaling during the bone metastasis process was found to enhance proliferation, induce the epithelial-to-mesenchymal transition, promote the modulation of the extracellular matrix, enhance angiogenesis and immune tolerance and metastasize and thrive in the bone. Due to the complexity of Wnt pathways and of the landscape of this mineralized tissue, Wnt function during metastatic progression within bone is not yet fully understood. Therefore, we believe that a better understanding of these pathways and their roles in the development of bone metastasis could improve our understanding of the disease and may constitute fertile ground for potential therapeutics.
      Citation: Cells
      PubDate: 2022-12-05
      DOI: 10.3390/cells11233934
      Issue No: Vol. 11, No. 23 (2022)
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