Autophagy Modulation by Viral Infections Influences Tumor Development

Autophagy is a self-degradative process important for balancing cellular homeostasis at critical times in development and/or in response to nutrient stress. This is particularly relevant in tumor model in which autophagy has been demonstrated to have an important impact on tumor behavior. In one hand, autophagy limits tumor transformation of precancerous cells in early stage, and in the other hand, it favors the survival, proliferation, metastasis, and resistance to antitumor therapies in more advanced tumors. This catabolic machinery can be induced by an important variety of extra- and intracellular stimuli. For instance, viral infection has often been associated to autophagic modulation, and the role of autophagy in virus replication differs according to the virus studied. In the context of tumor development, virus-modulated autophagy can have an important impact on tumor cells’ fate. Extensive analyses have shed light on the molecular and/or functional complex mechanisms by which virus-modulated autophagy influences precancerous or tumor cell development. This review includes an overview of discoveries describing the repercussions of an autophagy perturbation during viral infections on tumor behavior.

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Hypoxia induced HIF1a-mediated O-GalNAc glycosylation of cytosolic O-GlcNAcylated proteins to regulate signaling pathways in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15739 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15739-e15739

Author(s):

Gerrit Wolters-Eisfeld ◽

Baris Mercanoglu ◽

Alina Strohmaier ◽

Cenap Guengoer ◽

Jakob R. Izbicki ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Stage ◽

Tumor Development ◽

Hek293 Cells ◽

Treatment Resistant ◽

Tn Antigen ◽

Cell Energy ◽

Hif Pathway ◽

The Impact

e15739 Background: Hypoxia induced reprogramming of cell energy metabolism and changes in glycosylation are hallmarks of cancer promoting the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development. We examined the impact of hypoxia on O-GalNAc glycosylation in human HEK293, PDAC cell lines and clinical specimens. Methods: We profiled the expression of 88 glycosylation related genes by qPCR in HEK293 cells subjected to hypoxia either induced by 1% O2 or 200 mm CoCl2 identifying key O-GalNAc glycosyltransferases downregulated. Functional assays and glycoprotein analysis displayed a pronounced rate of O-GalNAc modified cytosolic proteins derived from hypoxia treated cells and PDAC specimens. Glycosidase assays could validate specificity of detection method used. Aberrant glycotype could be induced by HIF pathway activator ML 228 and inhibited using Echinomycin. PTK and STK analysis of cell lysates displayed correlation between phosphorylation and O-glycosylation in hypoxic samples. Results: Mechanistically we could show, that hypoxia induced decreased levels of C1GALT1C1 results in reduced T-Synthase activity with subsequent expression of truncated O-glycans (Tn antigen). Differential O-GalNAc glycosylation is inducible using HIF pathway activator ML228 under normoxia and the effect is reversed using 5 µM Echinomycin under hypoxia underscoring the role of HIF1a regulated transcription. Interestingly, the pattern of Tn antigen modified proteins derived from hypoxic samples differs significantly from engineered COSMC deficient cells, displaying O-GalNAc moieties in addition to O-GlcNAc in cytosolic protein fractions. Conclusions: Our findings point to a novel crosstalk of O-GalNAc and O-GlcNAcylation under hypoxia extending the knowledge base of differential O-GalNAc glycosylation in pancreatic cancer.

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Zkscan3 affects erythroblast development by regulating the transcriptional activity of GATA1 and KLF1 in mice

Journal of Molecular Histology ◽

10.1007/s10735-021-10052-8 ◽

2021 ◽

Author(s):

Zixuan Li ◽

Binjie Sheng ◽

Tingting Zhang ◽

Tian Wang ◽

Dan Chen ◽

...

Keyword(s):

Significant Role ◽

Knockout Mice ◽

Transcriptional Activity ◽

Early Stage ◽

Quantitative Polymerase Chain Reaction ◽

Tumor Development ◽

Rna Seq ◽

Mice Model ◽

First Time

AbstractZKSCAN3 encodes a zinc-finger transcription factor that regulates the expression of important genes and plays a significant role in tumor development, pathogenesis, and metastasis. However, its biological functions under normal physiological conditions remain largely unknown. In our previous studies, using flow cytometry, we found that the deletion of Zkscan3 may cause abnormal erythropoiesis. In this study, we found that, in a Zkscan3 knockout mice model, the number of splenic early-stage (basophilic-erythroblasts) and late-stage (chromatophilic-erythroblasts to polychromatophilic-erythroblasts through orthochromatophilic-erythroblasts) erythroblasts increased, whereas the number of late erythroblasts in the bone marrow decreased. Moreover, the phenotype was exacerbated after treating mice with phenylhydrazine (PHZ), which causes severe hemolytic anemia. In the knockout mice treated with PHZ, the percentage of reticulocyte in the peripheral blood conspicuously increased, whereas MCHC and red blood cells decreased. Then, we performed RNA-seq and quantitative-polymerase chain reaction assay and found that the expression of GATA1 and Tiam1 in erythroblasts were upregulated, whereas KLF1 was downregulated. Luciferase assays showed that Zkscan3 inhibited the transcription of GATA1 and Tiam1 and promoted the expression of KLF1. Additionally, ChIP and CO-IP results confirmed that Zkscan3 directly interacts with GATA1 and inhibits its transcriptional activity in MEL cells. Our results demonstrate, for the first time, the significant role of Zkscan3 in physiological erythropoiesis through the interaction with GATA1, both at the DNA and protein level, and with Tiam1 and KLF1 at the DNA level.

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Biophysical principles of choanoflagellate self-organization

10.1101/659698 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ben T. Larson ◽

Teresa Ruiz-Herrero ◽

Stacey Lee ◽

Sanjay Kumar ◽

L. Mahadevan ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Biology ◽

Early Stage ◽

Self Organization ◽

Proliferating Cells ◽

Cell Lineages ◽

Biophysical Processes ◽

Salpingoeca Rosetta ◽

Shed Light

AbstractInspired by the patterns of multicellularity in choanoflagellates, the closest living relatives of animals, we quantify the biophysical processes underlying the morphogenesis of rosette colonies in the choanoflagellateSalpingoeca rosetta. We find that rosettes reproducibly transition from an early stage of 2D growth to a later stage of 3D growth, despite the underlying stochasticity of the cell lineages. We postulate that the extracellular matrix (ECM) exerts a physical constraint on the packing of proliferating cells, thereby sculpting rosette morphogenesis. Our perturbative experiments coupled with biophysical simulations demonstrates the fundamental importance of a basally-secreted ECM for rosette morphogenesis. In addition, this yields a morphospace for the shapes of these multicellular colonies, consistent with observations of a range of choanoflagellates. Overall, our biophysical perspective on rosette development complements previous genetic perspectives and thus helps illuminate the interplay between cell biology and physics in regulating morphogenesis.Significance statementComparisons among animals and their closest living relatives, the choanoflagellates, have begun to shed light on the origin of animal multicellularity and development. Here we complement previous genetic perspectives on this process by focusing on the biophysical principles underlying colony morphology and morphogenesis. Our study reveals the crucial role of the extracellular matrix in shaping the colonies and leads to a phase diagram that delineates the range of morphologies as a function of the biophysical mechanisms at play.

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The role of geographical clusters in the success of reward-based crowdfunding campaigns

The International Journal of Entrepreneurship and Innovation ◽

10.1177/1465750320918385 ◽

2020 ◽

pp. 146575032091838

Author(s):

Nunzia Carbonara

Keyword(s):

Empirical Study ◽

Early Stage ◽

Entrepreneurial Activity ◽

Common People ◽

Data Set ◽

Entrepreneurial Ventures ◽

Small Investors ◽

Shed Light ◽

Geographical Clusters

Crowdfunding is a relatively new phenomenon, which disrupted the classic way to fund a venture. It consists in retrieving the capital needed to start an entrepreneurial activity drawing funds from a large base of small investors – generally common people – rather than from the traditional financial sources. Although many studies have been conducted on this topic, little focus has been put on the geography of this phenomenon. This article addresses this issue analysing whether regions characterized by the presence of geographical clusters are able to raise the probability of a successful crowdfunding campaign for projects located there. Drawing on a data set of 792 crowdfunded projects, we conduct an empirical study aimed at studying the role played by geographical clusters in fostering the crowdfunding of new entrepreneurial ventures. The results offer insights into the phenomenon of crowdfunding and shed light on the role of geographical clusters in the success of reward-based crowdfunding campaigns of early-stage entrepreneurial projects.

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Emerging Role of l-Dopa Decarboxylase in Flaviviridae Virus Infections

Cells ◽

10.3390/cells8080837 ◽

2019 ◽

Vol 8 (8) ◽

pp. 837 ◽

Cited By ~ 3

Author(s):

Frakolaki ◽

Kalliampakou ◽

Kaimou ◽

Moraiti ◽

Kolaitis ◽

...

Keyword(s):

Viral Replication ◽

Viral Infections ◽

Physiological Role ◽

Inverse Correlation ◽

Dopa Decarboxylase ◽

Hcv Rna ◽

Virus Infections ◽

Peripheral Tissues ◽

Functional Complex

l-dopa decarboxylase (DDC) that catalyzes the biosynthesis of bioactive amines, such as dopamine and serotonin, is expressed in the nervous system and peripheral tissues, including the liver, where its physiological role remains unknown. Recently, we reported a physical and functional interaction of DDC with the major signaling regulator phosphoinosite-3-kinase (PI3K). Here, we provide compelling evidence for the involvement of DDC in viral infections. Studying dengue (DENV) and hepatitis C (HCV) virus infection in hepatocytes and HCV replication in liver samples of infected patients, we observed a negative association between DDC and viral replication. Specifically, replication of both viruses reduced the levels of DDC mRNA and the ~120 kDa SDS-resistant DDC immunoreactive functional complex, concomitant with a PI3K-dependent accumulation of the ~50 kDa DDC monomer. Moreover, viral infection inhibited PI3K-DDC association, while DDC did not colocalize with viral replication sites. DDC overexpression suppressed DENV and HCV RNA replication, while DDC enzymatic inhibition enhanced viral replication and infectivity and affected DENV-induced cell death. Consistently, we observed an inverse correlation between DDC mRNA and HCV RNA levels in liver biopsies from chronically infected patients. These data reveal a novel relationship between DDC and Flaviviridae replication cycle and the role of PI3K in this process.

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Reduction of Inflammatory C3 and C4 Complement Proteins in Severe COVID-19 Patients

10.21203/rs.3.rs-127493/v1 ◽

2020 ◽

Author(s):

Ali Ghazavi ◽

Ghasem Mosayebi ◽

Nafiesh Keshavarzian ◽

Somayeh Rabiemajd ◽

Ali Ganji

Keyword(s):

Blood Cells ◽

Viral Infections ◽

White Blood Cells ◽

Control Group ◽

Serum Samples ◽

Complement Proteins ◽

And Control ◽

The Complement System ◽

Shed Light

Abstract Background: The complement system, consisting of more than 20 soluble proteins, has a key role in innate immunity and inflammation that eliminates pathogens and viral infections. Therefore, we investigated the titer of C3, C4, and total IgG in the serum of the non-severe and severe COVID-19 patients. Methods: For this purpose, peripheral blood samples were collected from 30 non-sever, 30 severe COVID-19 patients, and 30 healthy individuals with similar age and sex as the control group. The amount of total IgG, C3, and C4 were analyzed in the serum samples. Also, white blood cells, platelets (PLTs), and lymphocytes were counted by the auto-analyzer. Results: White blood cells had no difference between patients and control groups. The results showed a significant decrease in lymphocyte and PLTs in COVID-19 patients compare to control. Complement proteins including C3 and C4 were increased in non-severe COVID-19 patients than the other groups. Total IgG showed a notable decrease in severe patients. In conclusion, the level of C3 and C4 complement proteins were increased in non-severe-COVID-19 patients; however, in the severe COVID-19 patients their concentrations were decreased. Conclusion: However, inflammatory C3 and C4 complement factors increase in non-severe COVID-19, it decreased in the severe patients that may be because of more consumption by the formation of the immune complex. These results can shed light on the inflammatory role of C3 and C4 proteins in various phases of the disease and could provide a basis for further exploration of the pathophysiological significance and can suggest them for specific interventions.

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The role of antibodies in the light of the theory of evolution

10.31219/osf.io/kp5dx ◽

2020 ◽

Author(s):

Helene Banoun

Keyword(s):

Viral Infections ◽

Cell Types ◽

Protective Role ◽

Theory Of Evolution ◽

Research And Teaching ◽

History Of ◽

Shed Light ◽

Antibody Secreting Cells ◽

Selection Of

The phenomenon of facilitation of viral infections by antibodies (ADE antibody dependent enhancement) as well as the resistance of agammaglobulinemia patients to certain viruses are in contradiction with the protective role of antibodies affirmed by classical immunology. This must be compared to the opsonizing antibodies that promote the specific phagocytosis of extra-cellular bacteria. However, questions about the role of antibodies have been raised since the beginning of the history of immunology. More recently, Pierre Sonigo has shed light on the contradictions between the finalist interpretation of the role of lymphocytes and the theory of evolution: how can it be explained that cells are selected to protect the organism they constitute? The role of anti-viral and anti-intracellular bacteria antibodies could be to allow phagocytosis by the cells: either directly by the Fc fragment of immunoglobulins, or via the complement for many cell types. This makes it easy to understand the selection of antibody- secreting cells. Natural selection favors the cells that produce the most affine Ig and thus guides the maturation of the proB cell to the plasma cell. A review of recent publications in theoretical immunology is consistent with this hypothesis. The theory of evolution should be integrated at every level of research and teaching in immunology, as it is for biology as a whole.

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Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms21207785 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7785

Author(s):

Guillaume Harlé ◽

Camille Kowalski ◽

Laure Garnier ◽

Stéphanie Hugues

Keyword(s):

Lymph Node ◽

T Cell ◽

Stromal Cells ◽

Viral Infections ◽

Immune Cell ◽

Tumor Development ◽

T Cell Immunity ◽

Cell Responses ◽

Cell Immunity

Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.

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The role of geographical clusters in the success of reward-based crowdfunding campaigns

The International Journal of Entrepreneurship and Innovation ◽

10.1177/1465750320915915 ◽

2020 ◽

Vol 21 (4) ◽

pp. 250-262 ◽

Cited By ~ 1

Author(s):

Carbonara Nunzia

Keyword(s):

Empirical Study ◽

Early Stage ◽

Geographical Area ◽

Data Set ◽

Entrepreneurial Ventures ◽

Shed Light ◽

Geographical Clusters

This article studies whether some salient characteristics of the geographical area in which a crowdfunding campaign is launched affect its success. Drawing on a data set of 792 crowdfunded projects, we conduct an empirical study aimed at studying the role played by geographical clusters (GCs) in fostering the crowdfunding of new entrepreneurial ventures. The results offer insights into the phenomenon of crowdfunding and shed light on the role of GCs in the success of reward-based crowdfunding campaigns of early-stage entrepreneurial projects.

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An Overview of the Role of Long Non-Coding RNAs in Human Choriocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22126506 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6506

Author(s):

Riccardo Di Fiore ◽

Sherif Suleiman ◽

Ana Felix ◽

Sharon A. O’Toole ◽

John J. O’Leary ◽

...

Keyword(s):

Current Knowledge ◽

Early Stage ◽

Female Genital Tract ◽

Tumor Development ◽

Good Prognosis ◽

Poorly Differentiated ◽

Novel Method ◽

Diverse Biological Activity ◽

Female Genital

Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer.

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