Csi-let-7a-5p delivered by extracellular vesicles from a liver fluke activates M1-like macrophages and exacerbates biliary injuries

2021 ◽  
Vol 118 (46) ◽  
pp. e2102206118
Author(s):  
Chao Yan ◽  
Qian-Yang Zhou ◽  
Jing Wu ◽  
Na Xu ◽  
Ying Du ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Extracellular Vesicles ◽  
Liver Fluke ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Critical Role ◽  
Clonorchis Sinensis ◽  
Long Distance ◽  
Proinflammatory Responses ◽  
Liver Flukes

Chronic infection with liver flukes (such as Clonorchis sinensis) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a-regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a-mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.

Microglia extracellular vesicles: focus on molecular composition and biological function

2021 ◽  
Vol 49 (4) ◽  
pp. 1779-1790 ◽  
Author(s):  
Lorenzo Ceccarelli ◽  
Chiara Giacomelli ◽  
Laura Marchetti ◽  
Claudia Martini
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Biological Effects ◽  
Genetic Material ◽  
Cell Communication ◽  
Molecular Composition ◽  
Cargo Proteins ◽  
A Cell ◽  
The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

scholarly journals Capn4 Enhances Osteopontin Expression through Activation of the Wnt/β-Catenin Pathway to Promote Epithelial Ovarian Carcinoma Metastasis

2017 ◽  
Vol 42 (1) ◽  
pp. 185-197 ◽  
Author(s):  
Xiaoming Yang ◽  
Jing Sun ◽  
Dandan Xia ◽  
Xupei Can ◽  
Lei Liu ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Epithelial Ovarian Carcinoma ◽  
Regulatory Subunit ◽  
Epithelial Tissue

Background and Aim: Increasing evidence shows that the calpain regulatory subunit Capn4 can modulate the proliferation and metastasis of cancer cells, and plays an important role in the development of malignant tumors. However, there is no information on the clinical significance of Capn4 in epithelial ovarian carcinoma (EOC) or the molecular mechanisms by which Capn4 promotes the growth and metastasis of EOC. Therefore, the aim of this study was to clarify the role of Capn4 in EOC. Methods: We evaluated Capn4 and osteopontin (OPN) expression in EOC cell lines and tissues from patients with ovarian cancer by western blotting and immunohistochemical analysis. We then created cell lines with downregulated and upregulated Capn4 expression, using Capn4-targeting small interfering RNA and a pcDNA3.1-Capn4 overexpression vector, respectively, to investigate its function in EOC in vitro. In addition, we investigated the potential mechanism underlying the function of Capn4 by examining the effect of modifying Capn4 expression on Wnt/β-catenin signaling pathway-related genes by western blotting. Results: Capn4 was overexpressed in clinical EOC tissues compared with that in normal ovarian epithelial tissue, and was associated with poor clinical outcomes. Upon silencing or overexpressing Capn4 in EOC cells, we concluded that Capn4 promotes cell proliferation and migration in vitro. Furthermore, Capn4 promoted EOC metastasis by interacting with the Wnt/β-catenin signaling pathway to upregulate OPN expression. Conclusion: Our study indicates that Capn4 plays a critical role in the progression and metastasis of EOC, and could be a potential therapeutic target for EOC management.

scholarly journals The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

2021 ◽  
Vol 23 (1) ◽  
pp. 430
Author(s):  
Ángel Ortega ◽  
Ivana Vera ◽  
Maria P. Diaz ◽  
Carla Navarro ◽  
Milagros Rojas ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Growth Regulation ◽  
Current Knowledge ◽  
Biological Effects ◽  
Critical Role ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Tumor Resistance ◽  
Therapeutic Alternatives

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

scholarly journals Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium

2019 ◽  
Vol 36 (4) ◽  
pp. 301-313
Author(s):  
Chenjian Song ◽  
Lingjing Liu ◽  
Junjie Chen ◽  
Yiran Hu ◽  
Jingli Li ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Airway Inflammation ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Pi3k Signaling Pathway ◽  
Cox 2

AbstractParticulate matter (PM) is an environmental pollutant closely associated with human airway inflammation. However, the molecular mechanisms of PM-related airway inflammation remains to be fully elucidated. It is known that COX-2/PGE2 play key roles in the pathogenesis of airway inflammation. Filaggrin is a transmembrane protein contributing to tight junction barrier function. As such, Filaggrin prevents leakage of transported solutes and is therefore necessary for the maintenance of epithelial integrity. The objective of the present study was to investigate the regulatory mechanisms of COX-2/PGE2 and Filaggrin upon PM exposure both in vivo and in vitro. C57BL/6 mice received intratracheal instillation of PM for two consecutive days. In parallel, human bronchial epithelial cells (HBECs) were exposed to PM for 24 h. PM exposure resulted in airway inflammation together with upregulation of COX-2/PGE2 and downregulation of Filaggrin in mouse lungs. Corresponding dysregulation of COX-2/PGE2 and Filaggrin was also observed in HBECs subjected to PM. PM exposure led to the phosphorylation of ERK, JNK, and PI3K signaling pathways in a time-dependent manner, while blockade of PI3K with the specific molecular inhibitor LY294002 partially reversed the dysregulation of COX-2/PGE2 and Filaggrin. Moreover, pretreatment of HBECs with NS398, a specific molecular inhibitor of COX-2, and AH6809, a downstream PGE2 receptor inhibitor, reversed the downregulation of Filaggrin upon PM exposure. Taken together, these data demonstrated that the PI3K signaling pathway upregulated COX-2 as well as PGE2 and acted as a pivotal mediator in the downregulation of Filaggrin.

scholarly journals Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 705 ◽  
Author(s):  
Beatriz Martins ◽  
Madania Amorim ◽  
Flávio Reis ◽  
António Francisco Ambrósio ◽  
Rosa Fernandes
Keyword(s):  
Diabetic Retinopathy ◽  
Extracellular Vesicles ◽  
Vision Loss ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Communication ◽  
Cell Junctions ◽  
Low Grade ◽  
Long Distance ◽  
Advanced Stages

Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.

scholarly journals The liver fluke Opisthorchis felineus as a group III or group I carcinogen

4open ◽  
2019 ◽  
Vol 2 ◽  
pp. 23 ◽  
Author(s):  
Mariya Yurievna Pakharukova ◽  
José Manuel Correia da Costa ◽  
Viatcheslav Alekseevitch Mordvinov
Keyword(s):  
Risk Factors ◽  
Russian Federation ◽  
Liver Fluke ◽  
Clonorchis Sinensis ◽  
Opisthorchis Felineus ◽  
Group Iii ◽  
Group I ◽  
Carcinogenic Potential ◽  
The Russian Federation ◽  
Liver Flukes

Opisthorchiasis caused by the liver fluke Opisthorchis felineus is one of the most common helminthic infections in the Russian Federation. The largest area affected by opisthorchiasis felinea occupies almost the entire territory of Western Siberia and extends to northern Kazakhstan and a part of the Ural region. Natural endemic regions of opisthorchiasis also exist in the European part of Russia, and in the regions of Western and Eastern Europe. According to the official statistics of the Russian Federation, up to 40 000 patients with opisthorchiasis are registered annually in the country. Opisthorchiasis felinea affects the hepatobiliary system and causes serious liver disorders, including cancer of the biliary tract. Other parasitoses, opisthorchiasis viverrini and clonorchiasis, are widespread in the Southeast Asia and China. The causative agents of these diseases, liver flukes O. viverrini and Clonorchis sinensis, are officially recognized as Group 1 biological carcinogens and are classified as the main risk factors for cholangiocarcinoma. O. felineus is included in Group 3 of biological carcinogens and is not officially considered carcinogenic to humans. Studies on the carcinogenic potential of this liver fluke and the epidemiology of cholangiocarcinoma in the Russian Federation have started in earnest quite recently. Nevertheless, we have some evidence that infection with O. felineus leads to a precancerous state of the bile duct epithelium. This state, combined with additional risk factors, poses a real risk of cholangiocarcinoma. In our opinion, taking into consideration the accumulated facts, the classification of the carcinogenic potential of O. felineus requires revision. In this review, we focus on the relevant characteristics of the biology and epidemiology of this helminth as well as experimental data on opisthorchiasis felinea; this information might clarify the carcinogenicity of O. felineus to humans.

scholarly journals Structure and characterization of the ribosomal transcription units of small liver flukes, Opisthorchis viverrini, O. Felineus and Clonorchis sinensis

2020 ◽  
Vol 17 (3) ◽  
pp. 441-447
Author(s):  
Le Thanh Hoa ◽  
Nguyen Thi Bich Nga ◽  
Doan Thi Thanh Huong ◽  
Le Thi Kim Xuyen ◽  
Nguyen Thi Khue
Keyword(s):  
Dna Sequences ◽  
Liver Fluke ◽  
Clonorchis Sinensis ◽  
Parasitic Infection ◽  
Nucleotide Sequences ◽  
Opisthorchis Viverrini ◽  
The Family ◽  
Liver Flukes ◽  
Family Classification

Opisthorchiasis is a zoonotic parasitic infection caused by small liver fluke species, Opisthorchis viverrini,O. felineus and Clonorchis sinensis, in the family Opisthorchiidae. Vietnam has both species, of which C.sinensis is distributed in the northern and O. viverrini in the central provinces. In addition to the mitochondrialgenomes, the ribosomal DNA sequences (rDNA) of these species are highly needed to obtain for providingmolecular markers in species identification, classification, phylogeny and evolutionary studies. In this study,the near/complete nucleotide sequences of ribosomal transcription units (rTU) from O. viverrini (Vietnamesesample), O. felineus (Russian sample) and C. sinensis (Vietnamese sample) were analyzed. All rTUs for threespecies were determined, which is 7,839 bp for O. viverrini, 6,948 bp for O. felineus and 7,296 bp for C.sinensis containing structures of 18S, ITS1, 5,8S, ITS2 and 28S. The IGS region was not obtained for all threespecies. In all three species, sequence analysis revealed 2 tandem repetitive elements of 47-48 bp/each in ITS1but not in ITS2. The nucleotide sequences of 18S, ITS1, ITS2 and 28S are valuable ribosomal markers that thisstudy provides for diagnosis, identification, taxonomic classification and population genetics. In conclusion,the rTU sequences for the three species of the family Opisthorchiidae have been identified and providesmolecular markers for the use of phylogenetic analysis for species/family classification in the superfamilyOpisthorchioidea and the class Trematoda.

scholarly journals Helminth infection-induced carcinogenesis: spectrometric insights from the liver flukes, Opisthorchis and Fasciola

2019 ◽  
Author(s):  
Maria João Gouveia ◽  
Maria Y. Pakharukova ◽  
Banchob Sripa ◽  
Gabriel Rinaldi ◽  
Paul J. Brindley ◽  
...  
Keyword(s):  
Dna Adducts ◽  
Liver Fluke ◽  
Helminth Infection ◽  
Fasciola Hepatica ◽  
Clonorchis Sinensis ◽  
Opisthorchis Viverrini ◽  
International Agency ◽  
Fresh Water Fish ◽  
Liver Flukes ◽  
Group 1

AbstractChronic infections with the flatworm parasites Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium are classified as group 1 biological carcinogens, i.e. definitive causes of cancer. In addition, we reported findings that support the inclusion of Opisthorchis felineus in this list of biological carcinogens. By contrast, infections with close phylogenetic relatives including Fasciola hepatica have not been associated with carcinogenesis. Earlier reports revealed of oxysterol metabolites of Opisthorchis liver fluke origin conjugated with DNA bases, suggesting that the generation of these DNA-adducts may underlie the mutagenicity and carcinogenicity of the infection with these food-borne pathogens. Here we employed liquid chromatography-mass spectrometry (LC-MS/MS) to investigate, compare and contrast spectrograms of soluble extracts from F. hepatica adult worms from bile ducts of cattle with those from O. viverrini and O. felineus from experimentally-infected hamsters. F. hepatica displayed a complex spectrophotometric profile. F. hepatica and Opisthorchis spp. shared several common compounds including oxysterol-like metabolites, bile acids and DNA-adducts, but the spectrometric profiles of these Opisthorchis species included far fewer compounds than F. hepatica. These findings support the postulate that oxysterol-like metabolites of parasite origin can initiate carcinogenesis and they point to a molecular basis for the inconsistencies among major groups of liver flukes concerning infection-induced malignancy.Author SummarySeveral species of trematodes are parasites of the human hepatobiliary tract. Infection with two of these flukes, Clonorchis sinsensis and Opisthorchis viverrini, fresh water fish-borne parasites that occur in East Asia is classified as group 1 carcinogens by the International Agency for Research on Cancer (IARC), i.e. definitive causes of cancer in humans. By contrast, infection with a different liver fluke, Fasciola hepatica, does not lead to malignant transformation of the biliary tract. Given the close phylogeny of all three parasites, this difference in carcinogenicity is intriguing and, if explained, likely of value in novel therapeutic approaches. The importance of the current findings is informative because they present a mass spectrometric analysis and catalog of the similarities and differences between fluke of the genus Opisthorchis and F. hepatica, potentially identifying carcinogenic metabolites of liver fluke origin. These metabolites can be expected to provide deeper understanding of helminth infection induced malignancy.

Extracellular Vesicles and Hematopoietic Stem Cell Aging

2021 ◽  
Author(s):  
Laura R. Goldberg
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Natural Aging ◽  
Cell Aging ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Effects Of Aging

Extracellular vesicles (EVs), important mediators of intercellular communication, play a critical role in modulating hematopoiesis within the bone marrow microenvironment. Although few studies have explicitly examined the connections between EVs and hematopoietic stem cell (HSC) aging, there is a growing body of evidence that implicates EVs in numerous age-related biologic processes and diseases. This, coupled with their tremendous capacity to influence hematopoiesis, suggests EVs may be key mediators of HSC aging. This review provides an overview of the effects of aging on HSCs, the role of EVs in aging in general, and then details key work in EV modulation of normal and malignant hematopoiesis, with a particular focus on how these effects may translate into the ability of EVs to drive HSC aging. Finally, it describes an exciting emerging literature that provides direct evidence for EV modulation of HSC phenotypes during natural aging and highlights their potential in HSC rejuvenation. Taken collectively, this body of research has profound implications for the future of HSC aging studies. More clearly defining how EVs modify HSC function in an age-dependent fashion and determining the molecular mechanisms by which they drive these age-related HSC phenotype changes will undoubtedly yield innovative strategies to delay or even reverse age-related hematologic dysfunction.

chGRP78 is Required for the Activation and Phosphorylation of AKT1 at Serine 478 in Chicken Sells

2021 ◽  
Author(s):  
H. Choi ◽  
Y.D. Kim ◽  
S.K. Jung ◽  
S. Sureshkumar ◽  
K.B. Oh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Binding Sites ◽  
Chicken Embryo ◽  
Molecular Mechanisms ◽  
Chicken Embryo Fibroblast ◽  
Critical Role ◽  
Fibroblast Cells ◽  
Chicken Serum ◽  
2D Gel ◽  
Chicken Fibroblast

Background: Chicken serum-mediated proliferation regulates chGRP78 to prevent apoptosis in chicken cells via chGRP78-mediated anti-apoptosis. However, the precise molecular mechanisms underlying the chGRP78-mediated protection against apoptosis remain undefined. In an earlier study, we have shown that chGRP78 is critical for chicken embryo fibroblast (CEF) and DF-1 cell proliferation.Methods: In this experiment, we highlight AKT1 as a key target of GRP78 during apoptosis. We used 2D gel-based proteomics and bioinformatics prediction analysis for our studies. Result: Here, we detected chGRP78 binding sites in AKT1-rgulated proteins. chGRP78 promoted AKT1 activation and chGRP78 silencing decreased AKT1 levels. Taken together, we suggest that the AKT1-mediated signaling pathway plays a critical role in GRP78-stimulated fibroblast survival and anti-apoptosis. Our findings have important implications for the maintenance of chicken fibroblast cells via the inhibition of apoptosis.

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