Search results for "serine"
showing 10 items of 590 documents
Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation
2020
Abstract The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomali…
Role of the HIPPO pathway as potential key player in the cross talk between oncology and cardiology.
2021
The HIPPO pathway (HP) is a highly conserved kinase cascade that affects organ size by regulating proliferation, cell survival and differentiation. Discovered in Drosophila melanogaster to early 2000, it immediately opened wide frontiers in the field of research. Over the last years the field of knowledge on HP is quickly expanding and it is thought will offer many answers on complex pathologies. Here, we summarized the results of several studies that have investigated HP signaling both in oncology than in cardiology field, with an overview on future perspectives in cardiology research.
Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis.
2017
The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF…
Discovery and Biological Evaluation of Potent and Selective N-Methylene Saccharin-Derived Inhibitors for Rhomboid Intramembrane Proteases
2017
Rhomboids are intramembrane serine proteases and belong to the group of structurally and biochemically most comprehensively characterized membrane proteins. They are highly conserved and ubiquitously distributed in all kingdoms of life and function in a wide range of biological processes, including epidermal growth factor signaling, mitochondrial dynamics, and apoptosis. Importantly, rhomboids have been associated with multiple diseases, including Parkinson's disease, type 2 diabetes, and malaria. However, despite a thorough understanding of many structural and functional aspects of rhomboids, potent and selective inhibitors of these intramembrane proteases are still not available. In this …
Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors
2017
Abstract Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styry…
Searching for Chymase Inhibitors among Chamomile Compounds Using a Computational-Based Approach
2018
Inhibitors of chymase have good potential to provide a novel therapeutic approach for the treatment of cardiovascular diseases. We used a computational approach based on pharmacophore modeling, docking, and molecular dynamics simulations to evaluate the potential ability of 13 natural compounds from chamomile extracts to bind chymase enzyme. The results indicated that some chamomile compounds can bind to the active site of human chymase. In particular, chlorogenic acid had a predicted binding energy comparable or even better than that of some known chymase inhibitors, interacted stably with key amino acids in the chymase active site, and appeared to be more selective for chymase than other …
Phosphorylation and proteasome recognition of the mRNA- binding protein Cth2 facilitates yeast adaptation to iron deficiency
2018
Iron is an indispensable micronutrient for all eukaryotic organisms due to its participation as a redox cofactor in many metabolic pathways. Iron imbalance leads to the most frequent human nutritional deficiency in the world. Adaptation to iron limitation requires a global reorganization of the cellular metabolism directed to prioritize iron utilization for essential processes. In response to iron scarcity, the conserved Saccharomyces cerevisiae mRNA-binding protein Cth2, which belongs to the tristetraprolin family of tandem zinc finger proteins, coordinates a global remodeling of the cellular metabolism by promoting the degradation of multiple mRNAs encoding highly iron-consuming proteins.…
Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease
2016
International audience; Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinsons disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model. To explore the function of LRRK2 variants in vivo, we …
Recent advances on CDK inhibitors: An insight by means of in silico methods
2017
The cyclin dependent kinases (CDKs) are a small family of serine/threonine protein kinases that can act as a potential therapeutic target in several proliferative diseases, including cancer. This short review is a survey on the more recent research progresses in the field achieved by using in silico methods. All the "armamentarium" available to the medicinal chemists (docking protocols and molecular dynamics, fragment-based, de novo design, virtual screening, and QSAR) has been employed to the discovery of new, potent, and selective inhibitors of cyclin dependent kinases. The results cited herein can be useful to understand the nature of the inhibitor-target interactions, and furnish an ins…
The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis
2020
Summary: Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in inf…