Moyamoya disease is an idiopathic chronically progressive cerebrovascular disease, which causes both ischemic and hemorrhagic stroke. Genetic studies identified RNF213/Mysterin and GUCY1A3 as disease-causing genes. They were also known to be associated with non-moyamoya intracranial large artery disease, coronary artery disease and pulmonary artery hypertension. This review focused on these two molecules and their strong linker, calcineurin/NFAT signaling and caveolin to understand the pathophysiology of moyamoya disease and related vascular diseases. They are important regulators of lipid metabolism especially lipotoxicity, NF-κB mediated inflammation, and nitric oxide-mediated vascular protection. Although intimal thickening with fibrosis and damaged vascular smooth muscle cells are the distinguishing features of moyamoya disease, origin of the fibrous tissue and the mechanism of smooth muscle cell damages remains not fully elucidated. Endothelial cells and smooth muscle cells have long been a focus of interest, but other vascular components such as immune cells and extracellular matrix also need to be investigated in future studies. Molecular research on moyamoya disease would give us a clue to understand the mechanism preserving vascular stability.

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RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability.

Spices can be used in cooking to enhance the flavor of food. In order to systematically summarize and discuss the flavor components of 29 elegant spices, the free amino acids, nucleotides, and organic acids in these spices were detected by high-performance liquid chromatography. Cluster analysis was carried out to classify the 29 elegant spices based on similar data. The results showed considerable variations in the total free amino acids (1.12‒31.59 g/kg), organic acids (9.63‒71.90 g/kg), and nucleotides (0.03‒2.72 g/kg) in the elegant spices. Nine of the amino acids, especially glutamic acid and arginine, were found to have a taste active value (TAV) greater than 1. The TAVs of the 5'-nucleotides, succinic acid, oxalic acid, tartaric acid, and ascorbic acid were all >1. The equivalent umami concentration (EUC) of sweet marjoram was 83.69 g MSG/100 g. The 29 elegant spices were divided into two categories according to cluster analysis of the EUC. Oregano fell into one category, and the remaining 28 spices fell into the other category.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/fsn3.1667

Determination of free amino acids, organic acids, and nucleotides in 29 elegant spices.

Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanated from receptor tyrosine kinases. However, recent evidence demonstrates that a misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.

Recent advances in PTP1B signaling in metabolism and cancer.

The role of microRNA-34 family in Alzheimer’s disease: A potential molecular link between neurodegeneration and metabolic disorders

RNF213 is a giant E3 ubiquitin ligase and a major susceptibility factor of Moyamoya disease, a cerebrovascular disorder that can result in stroke or death. In the cell, RNF213 is involved in lipid droplet formation, lipotoxicity, hypoxia, and NF-κB signaling, but its exact function in these processes is unclear. Structural characterization has revealed the presence of a dynein- like ATPase module and an unprecedented but poorly understood E3 module. Here, we demonstrate that RNF213 E3 activity is dependent on ATP binding, rather than ATP hydrolysis, and is particularly responsive to the ATP/ADP/AMP ratio. Biochemical and activity-based probe analyses identify a non-canonical zinc finger domain as the E3 active site, which utilizes the strictly conserved Cys4462, not involved in zinc coordination, as the reactive nucleophile. The cryo-EM structure of the trapped RNF213:E2∼Ub intermediate reveals RNF213 C-terminal domain as the E2 docking site, which positions the ubiquitin-loaded E2 proximal to the catalytic zinc finger, facilitating nucleophilic attack of Cys4462 on the E2∼Ub thioester. Our findings show that RNF213 represents an undescribed type of a transthiolation E3 enzyme and is regulated by adenine nucleotide concentration via its ATPase core, possibly allowing it to react to changing metabolic conditions in the cell.

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E3 ubiquitin ligase RNF213 employs a non-canonical zinc finger active site and is allosterically regulated by ATP

New insights into TNFα/PTP1B and PPARγ pathway through RNF213- a link between inflammation, obesity, insulin resistance, and Moyamoya disease.

Wild-type Canton-S flies of Drosophila melanogaster were treated with ellagic acid at 100 μM and 200 μM concentrations. Longevity assay showed male flies fed with 200 μM ellagic acid displayed longer mean lifespan and maximum lifespan than control flies. Female flies fed with 200 μM ellagic acid laid less number of eggs than control. The eclosion time was less in female flies fed with 200 μM ellagic acid. Ellagic acid fed female flies performed better than male flies and control flies for heat shock tolerance and starvation stress. Male flies treated with 100 μM ellagic acid recovered faster from cold shock compared with control flies. Male and female flies treated with ellagic acid displayed increased survival following exposure to 5% hydrogen peroxide. Gene expression studies displayed upregulated expressions of CAT, dFOXO, ATG1, and SOD2 in ellagic acid–treated male flies, and upregulated expressions of dFOXO, CAT, and SOD2 in ellagic acid–treated female flies. Results from these studies show the pro-longevity effect of ellagic acid on Drosophila melanogaster.

/pdf/ellagic-acid-prolongs-the-lifespan-of-drosophila-2zzryagq71.pdf

Ellagic acid prolongs the lifespan of Drosophila melanogaster

Modulatory functions of bioactive fruits, vegetables and spices in adipogenesis and angiogenesis

Dynamics of HOX gene expression and regulation in adipocyte development.

Diabetic patients are always at a higher risk of ischemic diseases like coronary artery diseases. One such ischemic carotid artery disease is Moyamoya. Moyamoya disease (MMD) has been associated with diabetes Type-I and II and the causality was unclear. RNF213 is the major susceptible gene for MMD. To understand the association between diabetes mellitus and MMD we chose the major players from both the anomalies, insulin and RNF213. But before establishing a role of RNF213 in insulin regulating pathway we had to understand the involvement of RNF213 within different biological systems. For this we have adopted a preliminary computational approach to understand the prominent interactions of RNF213. Our first objective was to construct an interactome for RNF213. We have analyzed several curated databases and adapted a list of RNF213 interacting partners to develop its interactome. Then to understand the involvement of this interactome in biological functions we have analyzed major biological pathways, biological processes and prominent clusters related to this interactome through computational approach. Then to develop a pathway that might give clue for RNF213 involvement in insulin regulatory pathway we have validated the intercluster and intracluster predictions and identified a regulatory pathway for RNF213. RNF213 interactome was observed to be involved in adaptive immunity with 4 major clusters; one of the cluster involved TNFα. Immune system involves several pathways, and therefore at this point we have chosen an event-based strategy to obtain an explicit target. Immunity is mediated by many pro-inflammatory cytokines like TNFα. TNFα-mediated inflammation, obesity and insulin resistance are associated. Therefore we chose to explore the role of RNF213 in TNFα-mediated inflammation in macrophages and inflammation-mediated insulin-resistance in adipocytes. We have observed an enhancement of RNF213 gene expression by LPS mediated pro-inflammatory stimuli and suppression by PPARγ-mediated anti-inflammatory, insulin sensitizing stimuli in macrophages. A more significant response was observed in adipocytes as well. Administration of the pro-inflammatory cytokine TNFα was able to impede the reduction in RNF213 expression during adipogenesis and this effect was observed to be mediated by PTP1B. Inactivation of PTP1B abolished RNF213 expression which in turn enhanced the adipogenesis process through enhanced PPARγ. Constitutive expression of RNF213 suppressed the adipocyte differentiation by the inhibition of PPARγ. We could show the expression of RNF213 has been regulated by TNFα/PTP1B pathway and PPARγ. The constitutive expression of RNF213 during adipogenesis appears to be an adipostatic measure that obese patients acquire to inhibit further adipogenesis. This is verified in silico by analyzing the gene expression data obtained from Gene Expression Omnibus database, which showed a higher expression of RNF213 in adipose tissue samples of obese people. Overall this study gives new insights in the TNFα-mediated pathway in adipogenesis and suggests a role of RNF213 in adipogenesis via this pathway.View Full Text

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Priyanka Sarkar

Papers

New insights into TNFα/PTP1B and PPARγ pathway through RNF213- a link between inflammation, obesity, insulin resistance, and Moyamoya disease.

Ellagic acid prolongs the lifespan of Drosophila melanogaster

Modulatory functions of bioactive fruits, vegetables and spices in adipogenesis and angiogenesis

Dynamics of HOX gene expression and regulation in adipocyte development.

New insights into TNFα/PTP1B and PPARγ pathway through RNF213- a link between inflammation, obesity, insulin resistance and Moyamoya disease