Search results for " Aggregation"

Causes and consequences of DNA damage-induced autophagy.

2021

Abstract Autophagy is a quality control pathway that maintains cellular homeostasis by recycling surplus and dysregulated cell organelles. Identification of selective autophagy receptors demonstrated the existence of pathways that selectively degrade organelles, protein aggregates or pathogens. Interestingly, different types of DNA damage can induce autophagy and autophagy-deficiency leads to genomic instability. Recent studies provided first insights into the pathways that connect autophagy with the DNA damage response. However, the physiological role of autophagy and the identity of its targets after DNA damage remain enigmatic. In this review, we summarize recent literature on the target…

Feedback Regulation of Syk by Protein Kinase C in Human Platelets

2019

The spleen tyrosine kinase (Syk) is essential for immunoreceptor tyrosine-based activation motif (ITAM)-dependent platelet activation, and it is stimulated by Src-family kinase (SFK)-/Syk-mediated phosphorylation of Y352 (interdomain-B) and Y525/526 (kinase domain). Additional sites for Syk phosphorylation and protein interactions are known but remain elusive. Since Syk S297 phosphorylation (interdomain-B) was detected in platelets, we hypothesized that this phosphorylation site regulates Syk activity via protein kinase C (PKC)-and cyclic adenosine monophosphate (cAMP)-dependent pathways. ADP, the GPVI-agonist convulxin, and the GPIb&alpha

Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulates autophagy-associated protein breakdown

2018

Summary: Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c−/− muscles. In addition, w…

Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

2017

The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibito…

Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model.

2019

Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer’s as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post-TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effe…

Back to the oligomeric state: pH-induced dissolution of concanavalin A amyloid-like fibrils into non-native oligomers

2016

The subtle interplay between long range electrostatic forces, hydrophobic interactions and short range protein-protein interactions regulates the onset/evolution of protein aggregation processes as well as the stability of protein supramolecular structures. Using a combination of FTIR spectroscopy, light scattering and advanced imaging, we present evidence on the main role of electrostatic forces in the formation and stability of amyloid-like fibrils formed from concanavalin A (ConA), a protein showing structural homology with the human serum amyloid protein. At high protein concentration, where protein-protein interactions cannot be neglected, we highlight a thermal-induced aggregation pat…

2017

Proteins containing glutamine repeats (polyQ) are known to be structurally unstable. Abnormal expansion of polyQ in some proteins exceeding a certain threshold leads to neurodegenerative disease, a symptom of which are protein aggregates. This has led to extensive research of the structure of polyQ stretches. However, the accumulation of contradictory results suggests that protein context might be of importance. Here we aimed to evaluate the structural context of polyQ regions in proteins by analysing the secondary structure of polyQ proteins and their homologs. The results revealed that the secondary structure in polyQ vicinity is predominantly random coil or helix. Importantly, the region…

Épidémiologie du cancer du pancréas

2018

Actually, pancreatic cancer is a major challenge in digestive oncology. Its prognosis remains very poor with a five-year net survival less than 10%. Although if pancreatic cancer incidence was low, data from French digestive cancer registries show a dramatic increase in recent years, more marked in women (annual variation of +3.6% between 1982 and 2012) than in men (+2.3%). The currently recognized risk factors like tobacco or obesity cannot explain this evolving epidemiology. Moreover, progress in understanding pancreatic carcinogenesis is still insufficient. Except for familial aggregation, systematic screening couldn't be proposed.

2017

Human neurodegenerative diseases are accompanied by accumulation of heavily oxidized and aggregated proteins. However, the exact molecular reason is not fully elucidated yet. Insufficient cellular protein quality control is thought to play an important role in accumulating covalently oxidized misfolded proteins. Pharmacologically active polyphenols and their derivatives exhibit potential for preventive and therapeutic purposes against protein aggregation during neurodegeneration. Although these compounds act on various biochemical pathways, their role in stabilizing the protein degradation machinery at different stages may be an attractive therapeutical strategy to halt the accumulation of …

Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis

2021

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated…