scholarly journals Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9043
Author(s):  
Maria Mercado-Gómez ◽  
Fernando Lopitz-Otsoa ◽  
Mikel Azkargorta ◽  
Marina Serrano-Maciá ◽  
Sofia Lachiondo-Ortega ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Function ◽  
Gene Array ◽  
Matrix Proteins ◽  
Nuclear Antigen ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Ubiquitin System ◽  
Proliferating Cell

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.

scholarly journals Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish

2019 ◽  
Vol 6 (2) ◽  
pp. 16 ◽  
Author(s):  
Suneeta Narumanchi ◽  
Karri Kalervo ◽  
Sanni Perttunen ◽  
Hong Wang ◽  
Katariina Immonen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Regeneration ◽  
Nuclear Antigen ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Tissue Samples ◽  
Micro Rnas ◽  
Proliferating Cell ◽  
Zebrafish Heart

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration.

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes

2019 ◽  
Vol 47 (1) ◽  
pp. 357-370 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Daniela Corda
Keyword(s):  
Intracellular Transport ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Intracellular Traffic ◽  
Adp Ribosylation ◽  
Cell Responses ◽  
Physiological Processes ◽  
Dependent Cell ◽  
Ribose Moiety

AbstractADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress or starvation. An emerging role of the PARPs is their control of intracellular transport, as it is the case for tankyrases/PARP5 and PARP12. Here, we discuss the evidence pointing at this novel aspect of PARPs-dependent cell regulation.

scholarly journals The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): An Overview of Its Impact on Obesity and Early Progression of Renal Pathology

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1748 ◽  
Author(s):  
Arianna Bettiga ◽  
Francesco Fiorio ◽  
Federico Di Marco ◽  
Francesco Trevisani ◽  
Annalisa Romani ◽  
...  
Keyword(s):  
Chronic Diseases ◽  
Advanced Glycation End Products ◽  
Cell Function ◽  
Advanced Glycation ◽  
Covalent Bonds ◽  
Physiological Processes ◽  
Glycation End Products ◽  
End Products ◽  
And Function

Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients’ everyday lives.

Cellular aspects of pathogenesis of hypertrophic cardiomyopathy: Role of cardiomyocyte polyploidy and activation of nuclear antigen of the proliferating cell in myocardium

2007 ◽  
Vol 1 (6) ◽  
pp. 582-588 ◽  
Author(s):  
E. V. Shlyakhto ◽  
L. A. Bokeria ◽  
M. G. Rybakova ◽  
E. N. Semernin ◽  
G. V. Selivanova ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Nuclear Antigen ◽  
Proliferating Cell

Role of AT1 angiotensin II receptors in renal ischemic injury

1998 ◽  
Vol 274 (1) ◽  
pp. F79-F90 ◽  
Author(s):  
Jimmy Kontogiannis ◽  
Kevin D. Burns
Keyword(s):  
Serum Creatinine ◽  
Ischemia Reperfusion ◽  
Renin Angiotensin System ◽  
Ischemic Injury ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Receptor Mrna ◽  
Proximal Tubular ◽  
Proliferating Cell

The present studies determined the effect of renal ischemia/reperfusion on components of the intrarenal renin-angiotensin system in rats and evaluated the effect of AT1angiotensin (ANG) II receptor blockade on functional recovery. After bilateral renal pedicle occlusion for 60 min, serum creatinine increased, peaking at 72 h, and returned to sham levels after 120 h. ANG II levels in ischemic kidneys were significantly increased 24 h after reperfusion but did not differ from levels in sham kidneys after 120 h. Both renal cortical angiotensinogen mRNA and proximal tubular AT1 receptor mRNA were significantly reduced early after reperfusion, returning to sham levels by 120 and 72 h, respectively. AT2ANG II receptor mRNA was undetectable in proximal tubules from sham rats but was consistently present in ischemic rats at 120 h. By histoautoradiography, we found that binding of125I-labeled ANG II was preserved in glomeruli but was decreased in whole cortex and outer medulla early after reperfusion and was completely blocked by the AT1 antagonist losartan. Treatment of rats with losartan (25 mg/kg sc daily), starting at the time of reperfusion, had no effect on expression of proliferating cell nuclear antigen in cortical tubules but caused a significant decrease in serum creatinine at 72 h (ischemia: 334 ± 69 μM vs. ischemia + losartan: 135 ± 28 μM; P < 0.025, n = 6). These data indicate that renal ischemic injury causes an early increase in intrarenal ANG II levels, associated with reduction of mRNA for angiotensinogen and proximal tubular AT1 receptors, and maintenance of glomerular ANG II binding. Losartan accelerates recovery of renal function, suggesting that activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.

scholarly journals Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling

2021 ◽  
Vol 15 ◽  
Author(s):  
Jissele A. Verdinez ◽  
Julien A. Sebag
Keyword(s):  
Plasma Membrane ◽  
Energy Homeostasis ◽  
Reproductive Function ◽  
Receptor Trafficking ◽  
Membrane Localization ◽  
Accessory Protein ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Glycosylation Sites

Prokineticin receptors are GPCRs involved in several physiological processes including the regulation of energy homeostasis, nociception, and reproductive function. PKRs are inhibited by the endogenous accessory protein MRAP2 which prevents them from trafficking to the plasma membrane. Very little is known about the importance of post-translational modification of PKRs and their role in receptor trafficking and signaling. Here we identify 2 N-linked glycosylation sites within the N-terminal region of PKR2 and demonstrate that glycosylation of PKR2 at position 27 is important for its plasma membrane localization and signaling. Additionally, we show that glycosylation at position 7 results in a decrease in PKR2 signaling through Gαs without impairing Gαq/11 signaling.

Characterization of cytosolic proliferating cell nuclear antigen (PCNA) in neutrophils: antiapoptotic role of the monomer

2013 ◽  
Vol 94 (4) ◽  
pp. 723-731 ◽  
Author(s):  
Alessia De Chiara ◽  
Magali Pederzoli-Ribeil ◽  
Julie Mocek ◽  
Céline Candalh ◽  
Patrick Mayeux ◽  
...  
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Proliferating Cell
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