scholarly journals The novel p.Gly306Asp perforin mutation causes Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL-2) probably due to a critical role of Gly306 in the pore-forming perforin domain.

2017 ◽  
Author(s):  
Ramón Urrea ◽  
Itziar Astigarraga ◽  
Ana Fernandez-Teijeiro ◽  
Carmen Rodriguez-Sainz ◽  
Maria Alonso-Martinez ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Critical Role ◽  
The Novel ◽  
Familial Hemophagocytic Lymphohistiocytosis

scholarly journals Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+ signaling in vascular endothelial cells

2018 ◽  
Vol 315 (5) ◽  
pp. H1477-H1485 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Hiromi Imamura ◽  
Joji Ando
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Atp Release ◽  
Vascular Endothelial ◽  
The Novel ◽  
Caveolin 1 ◽  
Atp Generation

Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications

2022 ◽  
Vol 23 ◽  
Author(s):  
Lin Yang ◽  
Zhixin Zhang ◽  
Doudou Wang ◽  
Yu Jiang ◽  
Ying Liu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Protein Complexes ◽  
Cell Metabolism ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Mtor Signaling

Abstract: The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.

Introduction: Religion and the Novel

2019 ◽  
pp. 3-33
Author(s):  
Christina Phillips
Keyword(s):  
Postcolonial Studies ◽  
Critical Role ◽  
Postcolonial Literature ◽  
The Other ◽  
The Novel ◽  
Religion And Literature ◽  
Religious Other ◽  
Role Of Religion ◽  
The Relationship

This chapter introduces the topic of religion and literature, theorises the novel as a secular genre, and develops a concept of religion as the other in the Arabic novel. It begins with a discussion of the relationship between religion and literature, identifying imagination, metaphorical language and mythos as areas of overlap, before turning to the question of religion and the Arabic novel as a modern form which eschews faith and dogma but is nevertheless packed with religious themes, images, characters, language and intertextuality. This is accounted for by the form’s secularism, which is theorised in terms of Charles Taylor’s conditions of belief. Literary secularism is not static and stable however, thus religion emerges as the other in the Egyptian novel, with all the ambivalence which alterity characteristically entails. This religious other calls into question postcolonial studies’ over-valorisation of the East/West binary insofar as it has obscured the critical role of religion in Arab postcolonial literature and identity.

scholarly journals Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan de Toro-Martín ◽  
Tamara Fernández-Marcelo ◽  
Águeda González-Rodríguez ◽  
Fernando Escrivá ◽  
Ángela M. Valverde ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Glycogen ◽  
Hormonal Control ◽  
Standard Diet ◽  
Major Organ ◽  
Mtorc1 Pathway

Abstract Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted during the last week of gestation. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased. This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Restoration of autophagy with rapamycin but not with glucagon, indicated no defect in autophagy machinery per se, but in signals triggered by glucagon. Taken together, these results support the notion that hyperinsulinemia is an important mechanism by which mobilization of liver glycogen by autophagy is defective in food-restricted animals. This early alteration in the hormonal control of liver glycogen autophagy may influence the risk of developing metabolic diseases later in life.

scholarly journals A Selective Role of Dietary Anthocyanins and Flavan-3-ols in Reducing the Risk of Type 2 Diabetes Mellitus: A Review of Recent Evidence

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 841 ◽  
Author(s):  
Britt Burton-Freeman ◽  
Michał Brzeziński ◽  
Eunyoung Park ◽  
Amandeep Sandhu ◽  
Di Xiao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Risk Reduction ◽  
Critical Role ◽  
Glucose Absorption ◽  
Diabetes Risk ◽  
Fiber Plant

Type 2 diabetes mellitus (T2DM) is the most common form of DM and its prevalence is increasing worldwide. Because it is a progressive disease, prevention, early detection and disease course modification are possible. Diet plays a critical role in reducing T2DM risk. Therapeutic dietary approaches routinely recommend diets high in plant foods (i.e., vegetables, fruits, whole-grains). In addition to essential micronutrients and fiber, plant-based diets contain a wide-variety of polyphenols, specifically flavonoid compounds. Evidence suggests that flavonoids may confer specific benefits for T2DM risk reduction through pathways influencing glucose absorption and insulin sensitivity and/or secretion. The present review assesses the relationship between dietary flavonoids and diabetes risk reduction reviewing current epidemiology and clinical research. Collectively, the research indicates that certain flavonoids, explicitly anthocyanins and flavan-3-ols and foods rich in these compounds, may have an important role in dietary algorithms aimed to address diabetes risk factors and the development of T2DM.

scholarly journals The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhaoji Pan ◽  
Yiqing Tian ◽  
Guoping Niu ◽  
Chengsong Cao
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Wound Repair ◽  
Critical Role ◽  
The Novel ◽  
Potential Biomarker ◽  
Underlying Mechanisms ◽  
Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

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