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Cells, Volume 8, Issue 6 (June 2019)

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Cover Story (view full-size image) HSP90s interact with and modulate several cellular signaling pathways involved in the regulation of [...] Read more.
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Open AccessReview
Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease
Received: 31 May 2019 / Revised: 21 June 2019 / Accepted: 24 June 2019 / Published: 25 June 2019
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Abstract
Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their [...] Read more.
Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their morphology to adapt to their environment. The microglial motility and morphological versatility are the result of a complex molecular machinery, mainly composed of mechanisms of organization of the actin cytoskeleton, coupled with a “sensory” system of membrane receptors that allow the cells to perceive changes in their microenvironment and modulate their responses. Evidence points to microglia as accountable for some of the changes observed in the brain during ageing, and microglia have a role in the development of neurodegenerative diseases, such as Alzheimer’s disease. The present review describes in detail the main mechanisms driving microglial motility in physiological conditions, namely, the cytoskeletal actin dynamics, with emphasis in proteins highly expressed in microglia, and the role of chemotactic membrane proteins, such as the fractalkine and purinergic receptors. The review further delves into the changes occurring to the involved proteins and pathways specifically during ageing and in Alzheimer’s disease, analyzing how these changes might participate in the development of this disease. Full article
(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)
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Open AccessArticle
The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites
Received: 18 April 2019 / Revised: 20 June 2019 / Accepted: 22 June 2019 / Published: 25 June 2019
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Abstract
Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for [...] Read more.
Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for cell fate. Vascular smooth muscle cell (VSMC) apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration. Though the successful autophagy of damaged mitochondria promotes VSMC survival against pro-apoptotic atherogenic stressors, it is unknown whether MAMs are involved in VSMC mitophagy processes. Here, we investigated the role of the multifunctional MAM protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating VSMC survival following a challenge by atherogenic lipids. Using high-resolution confocal microscopy and proximity ligation assays, we found an increase in MAM contacts as in PACS-2-associated MAMs upon stimulation with atherogenic lipids. Correspondingly, the disruption of MAM contacts by PACS-2 knockdown impaired mitophagosome formation and mitophagy, thus potentiating VSMC apoptosis. In conclusion, our data shed new light on the significance of the MAM modulatory protein PACS-2 in vascular cell physiopathology and suggest MAMs may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability. Full article
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Open AccessFeature PaperReview
Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis
Received: 23 May 2019 / Revised: 14 June 2019 / Accepted: 24 June 2019 / Published: 25 June 2019
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Abstract
Gastric cancer (GC) is one of the most wide-spread malignancies in the world. The oncogenic role of signaling of fibroblast growing factors (FGFs) and their receptors (FGFRs) in gastric tumorigenesis has been gradually elucidated by recent studies. The expression pattern and clinical correlations [...] Read more.
Gastric cancer (GC) is one of the most wide-spread malignancies in the world. The oncogenic role of signaling of fibroblast growing factors (FGFs) and their receptors (FGFRs) in gastric tumorigenesis has been gradually elucidated by recent studies. The expression pattern and clinical correlations of FGF and FGFR family members have been comprehensively delineated. Among them, FGF18 and FGFR2 demonstrate the most prominent driving role in gastric tumorigenesis with gene amplification or somatic mutations and serve as prognostic biomarkers. FGF-FGFR promotes tumor progression by crosstalking with multiple oncogenic pathways and this provides a rational therapeutic strategy by co-targeting the crosstalks to achieve synergistic effects. In this review, we comprehensively summarize the pathogenic mechanisms of FGF-FGFR signaling in gastric adenocarcinoma together with the current targeted strategies in aberrant FGF-FGFR activated GC cases. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
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Open AccessArticle
BMP2 and TGF-β Cooperate Differently during Synovial-Derived Stem-Cell Chondrogenesis in a Dexamethasone-Dependent Manner
Received: 1 May 2019 / Revised: 18 June 2019 / Accepted: 20 June 2019 / Published: 25 June 2019
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Abstract
Recent studies highlighting mesenchymal stem cell (MSC) epigenetic memory suggest that a different differentiation medium may be required depending on the tissue of origin. As synovial-derived stem cells (SDSCs) attract interest we aimed to investigate the influence of TGF-β1, BMP-2 and dexamethasone on [...] Read more.
Recent studies highlighting mesenchymal stem cell (MSC) epigenetic memory suggest that a different differentiation medium may be required depending on the tissue of origin. As synovial-derived stem cells (SDSCs) attract interest we aimed to investigate the influence of TGF-β1, BMP-2 and dexamethasone on SDSC chondrogenesis in vitro. We demonstrate that dexamethasone-free medium led to enhanced chondrogenic differentiation at both the mRNA and matrix level. The greatest COL2A1/COL10A1 ratio was detected in cells exposed to a combination medium containing 10 ng/mL BMP-2 and 1 ng/mL TGF-β1 in the absence of dexamethasone, and this was reflected in the total amount of glycosaminoglycans produced. In summary, dexamethasone-free medium containing BMP-2 and TGF-β1 may be the most suitable when using SDSCs for cartilage tissue regeneration. Full article
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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Open AccessArticle
Activation of Slit2/Robo1 Signaling Promotes Tumor Metastasis in Colorectal Carcinoma through Activation of the TGF-β/Smads Pathway
Received: 28 March 2019 / Revised: 18 June 2019 / Accepted: 23 June 2019 / Published: 25 June 2019
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Abstract
Slit2 (slit guidance ligand 2), a ligand of the Roundabout1 (Robo1) transmembrane receptor, is often overexpressed in colorectal carcinomas (CRCs). In this study, we performed data mining in the Metabolic gEne RApid Visualizer (MERAV) database and found that Slit2 and TGF-β1 (Transforming growth [...] Read more.
Slit2 (slit guidance ligand 2), a ligand of the Roundabout1 (Robo1) transmembrane receptor, is often overexpressed in colorectal carcinomas (CRCs). In this study, we performed data mining in the Metabolic gEne RApid Visualizer (MERAV) database and found that Slit2 and TGF-β1 (Transforming growth factor-β1) are highly expressed in carcinomas relative to those in tumor-free tissues from healthy volunteers or wild type mice. Furthermore, expression of Slit2 and TGF-β1 in CRCs increases with pathological stages. Serum levels of Slit2 in patients with CRC and in ApcMin/+ mice with spontaneous intestinal adenoma were significantly increased compared with those in healthy controls. Specific blockage of Slit2 binding to Robo1 inactivated TGF-β/Smads signaling and inhibited tumor cell migration and metastasis, which can be partially restored by treatment with TGF-β1. However, specific inhibition of TGF-β1/Smads signaling reduced CRC tumor cell migration and invasion without affecting cell proliferation. This study suggests that activation of Slit2/Robo1 signaling in CRC induces tumor metastasis partially through activation of the TGF-β/Smads pathway. Full article
(This article belongs to the Section Cell Motility and Adhesion)
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Open AccessArticle
Relationship between Multiple Sclerosis-Associated IL2RA Risk Allele Variants and Circulating T Cell Phenotypes in Healthy Genotype-Selected Controls
Received: 29 May 2019 / Revised: 21 June 2019 / Accepted: 24 June 2019 / Published: 25 June 2019
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Abstract
Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with [...] Read more.
Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4+ but not CD8+ T cells. In CD4+ T cells, carriers of the risk genotype had a reduced frequency of CD25+ TFH1 cells (p = 0.001) and an increased frequency of CD25+ recent thymic emigrant cells (p = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4+ T cells (CD31CD45RA+), CD39+ TReg cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated IL2RA SNPs on expression of CD25 in CD4+ T cell subsets. Insight into the associations of MS-associated IL2RA SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Multiple Sclerosis)
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Open AccessArticle
Pooling of Patient-Derived Mesenchymal Stromal Cells Reduces Inter-Individual Confounder-Associated Variation without Negative Impact on Cell Viability, Proliferation and Osteogenic Differentiation
Received: 23 May 2019 / Revised: 7 June 2019 / Accepted: 21 June 2019 / Published: 24 June 2019
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Abstract
Patient-derived mesenchymal stromal cells (MSCs) play a key role in bone tissue engineering. Various donor-specific factors were identified causing significant variability in the biological properties of MSCs impairing quality of data and inter-study comparability. These limitations might be overcome by pooling cells of [...] Read more.
Patient-derived mesenchymal stromal cells (MSCs) play a key role in bone tissue engineering. Various donor-specific factors were identified causing significant variability in the biological properties of MSCs impairing quality of data and inter-study comparability. These limitations might be overcome by pooling cells of different donors. However, the effects of pooling on osteogenic differentiation, proliferation and vitality remain unknown and have, therefore, been evaluated in this study. MSCs of 10 donors were cultivated and differentiated into osteogenic lineage individually and in a pooled setting, containing MSCs of each donor in equal parts. Proliferation was evaluated in expansion (assessment of generation time) and differentiation (quantification of dsDNA content) conditions. Vitality was visualized by a fluorescence-microscopy-based live/dead assay. Osteogenic differentiation was assessed by quantification of alkaline phosphatase (ALP) activity and extracellular calcium deposition. Compared to the individual setting, generation time of pooled MSCs was shorter and proliferation was increased during differentiation with significantly lower variances. Calcium deposition was comparable, while variances were significantly higher in the individual setting. ALP activity showed high variance in both groups, but increased comparably during the incubation period. In conclusion, MSC pooling helps to compensate donor-dependent variability and does not negatively influence MSC vitality, proliferation and osteogenic differentiation. Full article
(This article belongs to the Special Issue Stem Cells in Personalized Medicine)
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Open AccessArticle
Berberine Promotes Beige Adipogenic Signatures of 3T3-L1 Cells by Regulating Post-transcriptional Events
Received: 21 May 2019 / Revised: 15 June 2019 / Accepted: 20 June 2019 / Published: 23 June 2019
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Abstract
Induced brown adipocytes (also referred to as beige cells) execute thermogenesis, as do the classical adipocytes by consuming stored lipids, being related to metabolic homeostasis. Treatment of phytochemicals, including berberine (BBR), was reported to induce conversion from white adipocytes to beige cells. In [...] Read more.
Induced brown adipocytes (also referred to as beige cells) execute thermogenesis, as do the classical adipocytes by consuming stored lipids, being related to metabolic homeostasis. Treatment of phytochemicals, including berberine (BBR), was reported to induce conversion from white adipocytes to beige cells. In this study, results of microRNA (miRNA)-seq analyses revealed a decrease in miR-92a, of which the transcription is driven by the c13orf25 promoter in BBR-treated 3T3-L1 cells. BBR treatment manipulated the expressions of SP1 and MYC, in turn, reducing the activity of the c13orf25 promoter. A decrease in miR-92a led to an increase in RNA-binding motif protein 4a (RBM4a) expression, which facilitated the beige adipogenesis. Overexpression of miR-92a or depletion of RBM4a reversely interfered with the impact of BBR treatment on the beige adipogenic signatures, gene expressions, and splicing events in 3T3-L1 cells. Our findings demonstrated that BBR treatment enhanced beige adipogenesis of 3T3-L1 cells through transcription-coupled post-transcriptional regulation. Full article
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Open AccessArticle
miR-26a-5p is a Stable Reference Gene for miRNA Studies in Chondrocytes from Developing Human Cartilage
Received: 17 May 2019 / Revised: 18 June 2019 / Accepted: 20 June 2019 / Published: 22 June 2019
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Abstract
miRNAs are emerging as key regulators of complex biological systems in several developmental processes. qRT-PCR is a powerful tool to quantitatively assess the profiles and modulation of miRNA expression. In the emerging field of cartilage maturation studies, from precursor to hypertrophic chondrocytes, few [...] Read more.
miRNAs are emerging as key regulators of complex biological systems in several developmental processes. qRT-PCR is a powerful tool to quantitatively assess the profiles and modulation of miRNA expression. In the emerging field of cartilage maturation studies, from precursor to hypertrophic chondrocytes, few data about miRNA regulation are available, and no consensus on the best reference gene (RG) has been reached. This is a crucial pitfall since reliable outcomes depend on proper data normalization. The aim of this work was to identify reliable and stable miRNA RGs, basing the analysis on available high throughput qRT-PCR miRNA data (from the NCBI Gene Expression Omnibus database, GSE49152) obtained from human embryonic cartilage tissues enriched in the precursor, differentiated, and hypertrophic chondrocytes. Four normalization approaches were used, and the stability was quantified by combining BestKeeper, delta-Ct, geNorm, and NormFinder statistical tools. An integrated approach allowed to identify miR-26a-5p as the most stable RG and miR-212-3p as the worst one. RNU44, used in original dataset analysis, performed as second best RG. Applications of different normalization strategies significantly impacted the profiles and modulation of miRNA expression. Herein presented results point out the crucial need of a consensus on data normalization studies aimed at dissecting miRNA role in human cartilage development, to avoid the postulation of unreliable biological conclusions. Full article
(This article belongs to the Special Issue Regulatory Functions of microRNAs)
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Open AccessReview
Role of Lipid Rafts in Hematopoietic Stem Cells Homing, Mobilization, Hibernation, and Differentiation
Received: 2 May 2019 / Revised: 7 June 2019 / Accepted: 14 June 2019 / Published: 22 June 2019
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Abstract
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of [...] Read more.
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of the HSCs act as the receptors and control platforms for these effectors. LRs are membrane microdomains that are enriched in cholesterol, sphingolipid, and proteins. They are involved in diverse cellular processes including morphogenesis, cytokinesis, signaling, endocytic events, and response to the environment. They are also involved in different types of diseases, such as cancer, Alzheimer’s, and prion disease. LR clustering and disruption contribute directly to the differentiation, homing, hibernation, or mobilization of HSCs. Thus, characterization of LR integrity may provide a promising approach to controlling the fate of stem cells for clinical applications. In this review, we show the critical role of LR modification (clustering, disruption, protein incorporation, and signal responding) in deciding the fate of HSCs, under the effect of soluble cytokines such as stem cell factor (SCF), transforming growth factor- β (TGF-β), hematopoietic-specific phospholipase Cβ2 (PLC-β2), and granulocyte colony-stimulating factor (G-CSF). Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
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Open AccessArticle
mTOR Signaling Pathway Regulates Sperm Quality in Older Men
Received: 5 June 2019 / Revised: 17 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand [...] Read more.
Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand the molecular mechanisms responsible for age-dependent decline in spermatozoa quality. To attain it, we evaluated the impact of male age on the activity of signaling proteins in two distinct spermatozoa populations: total spermatozoa fraction and highly motile/viable fraction. In older men, we observed an inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) in the highly viable spermatozoa population. On the contrary, when considering the entire spermatozoa population (including defective/immotile/apoptotic cells) our findings support an active mTORC1 signaling pathway in older men. Additionally, total spermatozoa fractions of older men presented increased levels of apoptotic/stress markers [e.g., cellular tumor antigen p53 (TP53)] and mitogen-activated protein kinases (MAPKs) activity. Moreover, we established that the levels of most signaling proteins analyzed were consistently and significantly altered in men older than 27 years of age. This study was the first to associate the mTOR signaling pathway with the age impact on spermatozoa quality. Additionally, we constructed a network of the sperm proteins associated with male aging, identifying TP53 as a central player in spermatozoa aging. Full article
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Open AccessCommunication
The Role of Adipose Tissue in the Pathogenesis and Therapeutic Outcomes of Inflammatory Bowel Disease
Received: 31 May 2019 / Revised: 16 June 2019 / Accepted: 18 June 2019 / Published: 21 June 2019
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Abstract
Though historically regarded as an inert energy store, adipose tissue is a complex endocrine organ, which is increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Accumulating evidence points to visceral adipose tissue and specifically to its mesenteric component, or “creeping fat” [...] Read more.
Though historically regarded as an inert energy store, adipose tissue is a complex endocrine organ, which is increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Accumulating evidence points to visceral adipose tissue and specifically to its mesenteric component, or “creeping fat” as impacting on the disease course through its immunomodulatory properties. On the one hand, mesenteric fat acts as a physical barrier to inflammation and is involved in controlling host immune response to translocation of gut bacteria. On the other hand, however, there exists a strong link between visceral fat and complicated course of the disease with unfavorable therapeutic outcomes. Furthermore, “creeping fat” appears to play different roles in different IBD phenotypes, with the greatest pathogenetic contribution probably to an ileal form of Crohn’s disease. In this review, we summarize and discuss the existing literature on the subject and identify high-priority areas for future research. It may be that a better understanding of the role of mesenteric fat in IBD will determine new therapeutic targets and translate into improved clinical outcomes. Full article
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Open AccessArticle
Bone Marrow Involvement in Melanoma. Potentials for Detection of Disseminated Tumor Cells and Characterization of Their Subsets by Flow Cytometry
Received: 23 May 2019 / Revised: 13 June 2019 / Accepted: 14 June 2019 / Published: 21 June 2019
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Abstract
Disseminated tumor cells (DTCs) are studied as a prognostic factor in many non-hematopoietic tumors. Melanoma is one of the most aggressive tumors. Forty percent of melanoma patients develop distant metastases at five or more years after curative surgery, and frequent manifestations of melanoma [...] Read more.
Disseminated tumor cells (DTCs) are studied as a prognostic factor in many non-hematopoietic tumors. Melanoma is one of the most aggressive tumors. Forty percent of melanoma patients develop distant metastases at five or more years after curative surgery, and frequent manifestations of melanoma without an identified primary lesion may reflect the tendency of melanoma cells to spread from indolent sites such as bone marrow (BM). The purpose of this work was to evaluate the possibility of detecting melanoma DTCs in BM based on the expression of a cytoplasmatic premelanocytic glycoprotein HMB-45 using flow cytometry, to estimate the influence of DTCs’ persistence in BM on hematopoiesis, to identify the frequency of BM involvement in patients with melanoma, and to analyze DTC subset composition in melanoma. DTCs are found in 57.4% of skin melanoma cases and in as many as 28.6% of stage I cases, which confirms the aggressive course even of localized disease. Significant differences in the groups with the presence of disseminated tumor cells (DTCs+) and the lack thereof (DTC) are noted for blast cells, the total content of granulocyte cells, and oxyphilic normoblasts of erythroid raw cells. Full article
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Open AccessReview
Inception Mechanisms of Tunneling Nanotubes
Received: 16 May 2019 / Revised: 18 June 2019 / Accepted: 18 June 2019 / Published: 21 June 2019
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Abstract
Tunneling nanotubes (TNTs) are thin membranous tubes that interconnect cells, representing a novel route of cell-to-cell communication and spreading of pathogens. TNTs form between many cell types, yet their inception mechanisms remain elusive. We review in this study general concepts related to the [...] Read more.
Tunneling nanotubes (TNTs) are thin membranous tubes that interconnect cells, representing a novel route of cell-to-cell communication and spreading of pathogens. TNTs form between many cell types, yet their inception mechanisms remain elusive. We review in this study general concepts related to the formation and stability of membranous tubular structures with a focus on a deviatoric elasticity model of membrane nanodomains. We review experimental evidence that tubular structures initiate from local membrane bending facilitated by laterally distributed proteins or anisotropic membrane nanodomains. We further discuss the numerical results of several theoretical and simulation models of nanodomain segregation suggesting the mechanisms of TNT inception and stability. We discuss the coupling of nanodomain segregation with the action of protruding cytoskeletal forces, which are mostly provided in eukaryotic cells by the polymerization of f-actin, and review recent inception mechanisms of TNTs in relation to motor proteins. Full article
(This article belongs to the Special Issue Frontiers in Cytoskeleton Research—From Development to Disease)
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Open AccessArticle
Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells
Received: 21 May 2019 / Revised: 14 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise [...] Read more.
The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs. Full article
(This article belongs to the Special Issue Stem Cells and Degenerative Diseases)
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Open AccessArticle
The Adenosine A2B Receptor Drives Osteoclast-Mediated Bone Resorption in Hypoxic Microenvironments
Received: 8 May 2019 / Revised: 12 June 2019 / Accepted: 20 June 2019 / Published: 21 June 2019
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Abstract
Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold [...] Read more.
Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O2) and A2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3–4, p < 0.05). The A2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis. Full article
(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)
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Open AccessArticle
Functionally Significant Features in the 5′ Untranslated Region of the ABCA1 Gene and Their Comparison in Vertebrates
Received: 3 April 2019 / Revised: 17 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
Single nucleotide polymorphisms located in 5′ untranslated regions (5′UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5′UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5′UTRs during gene evolution is scarce. Using [...] Read more.
Single nucleotide polymorphisms located in 5′ untranslated regions (5′UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5′UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5′UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (ABCA1) gene (Tangier disease), we describe our algorithm for functionally significant sequence finding. 5′UTR features (upstream start and stop codons, open reading frames (ORFs), GC content, motifs, and secondary structures) were studied using freely available bioinformatics tools in 55 vertebrate orthologous genes obtained from Ensembl and UCSC. The most conserved sequences were suggested as hot spots. Exon and intron enhancers and silencers (sc35, ighg2 cgamma2, ctnt, gh-1, and fibronectin eda exon), transcription factors (TFIIA, TATA, NFAT1, NFAT4, and HOXA13), some of them cancer related, and microRNA (hsa-miR-4474-3p) were localized to these regions. An upstream ORF, overlapping with the main ORF in primates and possibly coding for a small bioactive peptide, was also detected. Moreover, we showed several features of 5′UTRs, such as GC content variation, hairpin structure conservation or 5′UTR segmentation, which are interesting from a phylogenetic point of view and can stimulate further evolutionary oriented research. Full article
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
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Open AccessReview
Human Papilloma Virus-Associated Cervical Cancer and Health Disparities
Received: 7 May 2019 / Revised: 15 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
Cervical cancer develops through persistent infection with high-risk human papilloma virus (hrHPV) and is a leading cause of death among women worldwide and in the United States. Periodic surveillance through hrHPV and Pap smear-based testing has remarkably reduced cervical cancer incidence worldwide and [...] Read more.
Cervical cancer develops through persistent infection with high-risk human papilloma virus (hrHPV) and is a leading cause of death among women worldwide and in the United States. Periodic surveillance through hrHPV and Pap smear-based testing has remarkably reduced cervical cancer incidence worldwide and in the USA. However, considerable discordance in the occurrence and outcome of cervical cancer in various populations exists. Lack of adequate health insurance appears to act as a major socioeconomic burden for obtaining cervical cancer preventive screening in a timely manner, which results in disparate cervical cancer incidence. On the other hand, cervical cancer is aggressive and often detected in advanced stages, including African American and Hispanic/Latina women. In this context, our knowledge of the underlying molecular mechanism and genetic basis behind the disparate cervical cancer outcome is limited. In this review, we shed light on our current understanding and knowledge of racially disparate outcomes in cervical cancer. Full article
(This article belongs to the Special Issue HPV-Associated Malignancies: Screening, Prevention and Treatment)
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Open AccessReview
Patient-Derived Xenograft Models of Breast Cancer and Their Application
Received: 2 May 2019 / Revised: 6 June 2019 / Accepted: 18 June 2019 / Published: 20 June 2019
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Abstract
Recently, patient-derived xenograft (PDX) models of many types of tumors including breast cancer have emerged as a powerful tool for predicting drug efficacy and for understanding tumor characteristics. PDXs are established by the direct transfer of human tumors into highly immunodeficient mice and [...] Read more.
Recently, patient-derived xenograft (PDX) models of many types of tumors including breast cancer have emerged as a powerful tool for predicting drug efficacy and for understanding tumor characteristics. PDXs are established by the direct transfer of human tumors into highly immunodeficient mice and then maintained by passaging from mouse to mouse. The ability of PDX models to maintain the original features of patient tumors and to reflect drug sensitivity has greatly improved both basic and clinical study outcomes. However, current PDX models cannot completely predict drug efficacy because they do not recapitulate the tumor microenvironment of origin, a failure which puts emphasis on the necessity for the development of the next generation PDX models. In this article, we summarize the advantages and limitations of current PDX models and discuss the future directions of this field. Full article
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Open AccessFeature PaperReview
To See or Not to See: A Systematic Review of the Importance of Human Ocular Surface Cytokine Biosignatures in Ocular Allergy
Received: 15 May 2019 / Revised: 12 June 2019 / Accepted: 19 June 2019 / Published: 20 June 2019
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Abstract
Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such [...] Read more.
Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such as itchiness, watery eyes, irritation, and swelling. Given the recent research focus in optometry on the aetiology of corneal ectasia subtypes like keratoconus, there is an increasing need for the development of new clinical diagnostic methods. An increasing trend is evident among recent publications in cytokine studies, whereby the concentrations of cytokines in healthy and disease states are compared to derive a specific cytokine profile for that disease referred to as ‘biosignatures’. Biosignatures have diagnostic applications in ocular allergy as a cheap, non-invasive alternative to current techniques like IgE antibody testing and skin prick tests. Cytokine detection from tear samples collected via microcapillary flow can be analysed either by enzyme-linked immunosorbent assays (ELISA), multiplex magnetic bead assays, or immunoblot assays. Characterising patient hypersensitivities through diagnostic tests is the first step to managing exposure to triggers. Investigating cytokine biosignatures in ocular allergy and their links to physiology are imperative and will be the focus of this systematic review article. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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Open AccessReview
Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation
Received: 20 May 2019 / Revised: 12 June 2019 / Accepted: 19 June 2019 / Published: 20 June 2019
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Abstract
Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D2 (PGD2) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and [...] Read more.
Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D2 (PGD2) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and survival of leukocytes in various allergy-associated disorders. In the periphery, the hematopoietic PGD synthase (hPGDS) acts downstream of the arachidonic acid/COX pathway catalysing the isomerisation of PGH2 to PGD2, which makes it an interesting target to treat allergic inflammation. Although much effort has been put into developing efficient hPGDS inhibitors, no compound has made it to the market yet, which indicates that more light needs to be shed on potential PGD2 sources and targets to determine which particular condition and patient will benefit most and thereby improve therapeutic efficacy. In this review, we want to revisit current knowledge about hPGDS function, expression in allergy-associated cell types and their contribution to PGD2 levels as well as beneficial effects of hPGDS inhibition in allergic asthma, rhinitis, atopic dermatitis, food allergy, gastrointestinal allergic disorders and anaphylaxis. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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Open AccessArticle
Fibronectin Regulation of Integrin B1 and SLUG in Circulating Tumor Cells
Received: 24 May 2019 / Revised: 18 June 2019 / Accepted: 19 June 2019 / Published: 20 June 2019
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Abstract
Metastasis is the leading cause of cancer death worldwide. Circulating tumor cells (CTCs) are a critical step in the metastatic cascade and a good tool to study this process. We isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a [...] Read more.
Metastasis is the leading cause of cancer death worldwide. Circulating tumor cells (CTCs) are a critical step in the metastatic cascade and a good tool to study this process. We isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a human xenograft mouse model of castration-resistant prostate cancer (CRPC). From these models, novel primary tumor and CTC cell lines were established. CTCs exhibited greater migration than primary tumor-derived cells, as well as epithelial-to-mesenchymal transition (EMT), as observed from decreased E-cadherin and increased SLUG and fibronectin expression. Additionally, when fibronectin was knocked down in CTCs, integrin B1 and SLUG were decreased, indicating regulation of these molecules by fibronectin. Investigation of cell surface molecules and secreted cytokines conferring immunomodulatory advantage to CTCs revealed decreased major histocompatibility complex class I (MHCI) expression and decreased endostatin, C-X-C motif chemokine 5 (CXCL5), and proliferin secretion by CTCs. Taken together, these findings indicate that CTCs exhibit distinct characteristics from primary tumor-derived cells. Furthermore, CTCs demonstrate enhanced migration in part through fibronectin regulation of integrin B1 and SLUG. Further study of CTC biology will likely uncover additional important mechanisms of cancer metastasis. Full article
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Open AccessArticle
Protective Effects of Licochalcone A Improve Airway Hyper-Responsiveness and Oxidative Stress in a Mouse Model of Asthma
Received: 12 May 2019 / Revised: 18 June 2019 / Accepted: 19 June 2019 / Published: 20 June 2019
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Abstract
Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying [...] Read more.
Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma. Full article
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Open AccessArticle
Circular RNA circ-FoxO3 Inhibits Myoblast Cells Differentiation
Received: 1 May 2019 / Revised: 13 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
CircRNA is a type of closed circular non-coding RNA formed by reverse splicing and plays an important role in regulating the growth and development of plants and animals. To investigate the function of circ-FoxO3 in mouse myoblast cells’ (C2C12) differentiation and proliferation, we [...] Read more.
CircRNA is a type of closed circular non-coding RNA formed by reverse splicing and plays an important role in regulating the growth and development of plants and animals. To investigate the function of circ-FoxO3 in mouse myoblast cells’ (C2C12) differentiation and proliferation, we used RT-qPCR to detect the expression level of circ-FoxO3 in mouse myoblast cells at different densities and different differentiation stages, and the specific interference fragment was used to inhibit the expression level of circ-FoxO3 in myoblast cells to observe its effect on myoblast cells proliferation and differentiation. We found that the expression level of circ-FoxO3 in myoblast cells increased with the prolongation of myoblast cells differentiation time, and its expression level decreased with the proliferation of myoblast cells. At the same time, we found that the differentiation ability of the cells was significantly increased (p < 0.05), but the cell proliferation was unchanged (p > 0.05) after inhibiting the expression of circ-FoxO3 in myoblast cells. Combining the results of bioinformatics analysis and the dual luciferase reporter experiment, we found that circ-FoxO3 is a sponge of miR-138-5p, which regulates muscle differentiation. Our study shows that circ-FoxO3 can inhibit the differentiation of C2C12 myoblast cells and lay a scientific foundation for further study of skeletal muscle development at circRNA levels. Full article
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Open AccessArticle
ERBB2 Regulates MED24 during Cancer Progression in Mice with Pten and Smad4 Deletion in the Pulmonary Epithelium
Received: 13 May 2019 / Revised: 11 June 2019 / Accepted: 18 June 2019 / Published: 19 June 2019
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Abstract
ERBB2 is an oncogenic driver with frequent gene mutations and amplification in human lung tumors and is an attractive target for lung cancer therapy. However, target therapies can be improved by understanding the in vivo mechanisms regulated by ERBB2 during lung tumor development. [...] Read more.
ERBB2 is an oncogenic driver with frequent gene mutations and amplification in human lung tumors and is an attractive target for lung cancer therapy. However, target therapies can be improved by understanding the in vivo mechanisms regulated by ERBB2 during lung tumor development. Here, we generated genetic mouse models to show that Erbb2 loss inhibited lung tumor development induced by deletion of Pten and Smad4. Transcriptome analysis showed that Erbb2 loss suppressed the significant changes of most of the induced genes by ablation of Pten and Smad4. Overlapping with ERBB2-associated human lung cancer genes further identified those ERBB2 downstream players potentially conserved in human and mouse lung tumors. Furthermore, MED24 was identified as a crucial oncogenic target of ERBB2 in lung tumor development. Taken together, ERBB2 is required for the dysregulation of cancer-related genes, such as MED24, during lung tumor development. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
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Open AccessReview
Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors
Received: 15 May 2019 / Revised: 11 June 2019 / Accepted: 12 June 2019 / Published: 18 June 2019
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Abstract
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, [...] Read more.
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
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Open AccessReview
The Distinct Roles of CXCR3 Variants and Their Ligands in the Tumor Microenvironment
Received: 29 April 2019 / Revised: 14 June 2019 / Accepted: 16 June 2019 / Published: 18 June 2019
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Abstract
First thought to orchestrate exclusively leukocyte trafficking, chemokines are now acknowledged for their multiple roles in the regulation of cell proliferation, differentiation, and survival. Dysregulation of their normal functions contributes to various pathologies, including inflammatory diseases and cancer. The two chemokine receptor 3 [...] Read more.
First thought to orchestrate exclusively leukocyte trafficking, chemokines are now acknowledged for their multiple roles in the regulation of cell proliferation, differentiation, and survival. Dysregulation of their normal functions contributes to various pathologies, including inflammatory diseases and cancer. The two chemokine receptor 3 variants CXCR3-A and CXCR3-B, together with their cognate chemokines (CXCL11, CXCL10, CXCL9, CXCL4, and CXCL4L1), are involved in the control but also in the development of many tumors. CXCR3-A drives the infiltration of leukocytes to the tumor bed to modulate tumor progression (paracrine axis). Conversely, tumor-driven changes in the expression of the CXCR3 variants and their ligands promote cancer progression (autocrine axis). This review summarizes the anti- and pro-tumoral activities of the CXCR3 variants and their associated chemokines with a focus on the understanding of their distinct biological roles in the tumor microenvironment. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interaction and Metabolism)
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Open AccessArticle
Cortisol Excess-Mediated Mitochondrial Damage Induced Hippocampal Neuronal Apoptosis in Mice Following Cold Exposure
Received: 10 May 2019 / Revised: 31 May 2019 / Accepted: 14 June 2019 / Published: 18 June 2019
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Abstract
Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In [...] Read more.
Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In vitro, HT22 cells were treated with different concentrations of cortisol (CORT) for 3 h. In vivo, CORT levels in the hippocampus were measured using ELISA, western blotting, and immunohistochemistry to assess the neuronal population and oxidation of the hippocampus. In vitro, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy, and other methods were used to characterize the mechanism of mitochondrial damage induced by CORT. The phenomena of excessive CORT-mediated oxidation stress and neuronal apoptosis were shown in mouse hippocampus tissue following cold exposure, involving mitochondrial oxidative stress and endogenous apoptotic pathway activation. These processes were mediated by acetylation of lysine 9 of histone 3, resulting in upregulation involving Adenosine 5‘-monophosphate (AMP)-activated protein kinase (APMK) phosphorylation and translocation of Nrf2 to the nucleus. In addition, oxidation in male mice was more severe. These findings provide a new understanding of the underlying mechanisms of the cold stress response and explain the apoptosis process induced by CORT, which may influence the selection of animal models in future stress-related studies. Full article
(This article belongs to the Special Issue Differential Regulation of Glial and Neuronal Functions by TSPO)
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Open AccessReview
Delivery of microRNAs by Extracellular Vesicles in Viral Infections: Could the News be Packaged?
Received: 14 May 2019 / Revised: 4 June 2019 / Accepted: 13 June 2019 / Published: 18 June 2019
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Abstract
Extracellular vesicles (EVs) are released by various cells and recently have attracted attention because they constitute a refined system of cell–cell communication. EVs deliver a diverse array of biomolecules including messenger RNAs (mRNAs), microRNAs (miRNAs), proteins and lipids, and they can be used [...] Read more.
Extracellular vesicles (EVs) are released by various cells and recently have attracted attention because they constitute a refined system of cell–cell communication. EVs deliver a diverse array of biomolecules including messenger RNAs (mRNAs), microRNAs (miRNAs), proteins and lipids, and they can be used as potential biomarkers in normal and pathological conditions. The cargo of EVs is a snapshot of the donor cell profile; thus, in viral infections, EVs produced by infected cells could be a central player in disease pathogenesis. In this context, miRNAs incorporated into EVs can affect the immune recognition of viruses and promote or restrict their replication in target cells. In this review, we provide an updated overview of the roles played by EV-delivered miRNAs in viral infections and discuss the potential consequences for the host response. The full understanding of the functions of EVs and miRNAs can turn into useful biomarkers for infection detection and monitoring and/or uncover potential therapeutic targets. Full article
(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Disease)
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Open AccessArticle
Identification of Keratin 23 as a Hepatitis C Virus-Induced Host Factor in the Human Liver
Received: 9 April 2019 / Revised: 5 June 2019 / Accepted: 15 June 2019 / Published: 18 June 2019
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Abstract
Keratin proteins form intermediate filaments, which provide structural support for many tissues. Multiple keratin family members are reported to be associated with the progression of liver disease of multiple etiologies. For example, keratin 23 (KRT23) was reported as a stress-inducible protein, whose expression [...] Read more.
Keratin proteins form intermediate filaments, which provide structural support for many tissues. Multiple keratin family members are reported to be associated with the progression of liver disease of multiple etiologies. For example, keratin 23 (KRT23) was reported as a stress-inducible protein, whose expression levels correlate with the severity of liver disease. Hepatitis C virus (HCV) is a human pathogen that causes chronic liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma. However, a link between KRT23 and hepatitis C virus (HCV) infection has not been reported previously. In this study, we investigated KRT23 mRNA levels in datasets from liver biopsies of chronic hepatitis C (CHC) patients and in primary human hepatocytes experimentally infected with HCV, in addition to hepatoma cells. Interestingly, in each of these specimens, we observed an HCV-dependent increase of mRNA levels. Importantly, the KRT23 protein levels in patient plasma decreased upon viral clearance. Ectopic expression of KRT23 enhanced HCV infection; however, CRIPSPR/Cas9-mediated knockout did not show altered replication efficiency. Taken together, our study identifies KRT23 as a novel, virus-induced host-factor for hepatitis C virus. Full article
(This article belongs to the Special Issue Hepatitis C Virus and Host Interactions)
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