Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485

Rakhmanova, Valeriya; Jin, Mi rim; Shin, Jin‐Wook

doi:10.4110/in.2018.18.e18

Cited by 23 publications

(13 citation statements)

References 28 publications

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“…6). That mTOR is important for MC regranulation following MC degranulation is consistent with previous reports showing that activation of mTOR in MCs inhibited IgE mediated MC degranulation and cytokine release as well as their capacity to proliferate 52,53 . Presumably, activating mTOR triggers a metabolic switch in steady state MCs to accommodate regranulation which interferes with both degranulation and MC proliferation activities.…”

Section: Discussionsupporting

confidence: 92%

Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter

Iskarpatyoti

Shi

Rathor

et al. 2021

Preprint

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Mast cells (MCs) are highly granulated tissue resident hematopoietic cells and because of their capacity to degranulate and release many proinflammatory mediators, they are major effectors of chronic inflammatory disorders including asthma and urticaria. As MCs have the unique capacity to reform their granules following degranulation in vitro, their potential to undergo multiple cycles of degranulation and regranulation in vivo has been linked to their pathogenesis. However, it is not known what factors regulate MC regranulation let alone if MC regranulation occurs in vivo. Here, we report that IgE-sensitized mice can undergo multiple bouts of regranulation, following repeated anaphylactic reactions. mTORC1, a critical nutrient sensor that activates protein and lipid synthesis, was found necessary for MC regranulation. mTORC1 activity in MCs was regulated by a glucose-6-phosphate transporter, Slc37a2, which was found to be necessary for increased glucose-6-phosphate and ATP levels during regranulation, two upstream signals of mTOR. Slc37a2 is highly expressed at the cell periphery early during regranulation where it appears to colocalize with mTORC1. Additionally, this transporter was found to concentrate extracellular metabolites within endosomes which are trafficked directly into nascent granules. Thus, the metabolic switch associated with MC regranulation is mediated by the interactions of a cellular metabolic sensor and a transporter of extracellular metabolites into MC granules.

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Section: Discussionsupporting

confidence: 92%

Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter

Iskarpatyoti

Shi

Rathor

et al. 2021

Preprint

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“…Furthermore, Zhu et al showed that mTOR inhibition suppress eosinophil differentiation in allergic airway inflammation [64], Shin and coll. that reduces eosinophil infiltration and Th2 immune response [65] and Fang et al that IgE induced airway smooth muscle cell (ASMC) remodeling was significantly reduced by inhibition of mTOR [66] while Rakhmanova et al suggested as a therapeutic strategy for mast cell-related diseases the hyperactivation of mTORC1 [67]. The greater role of airway inflammation and remodeling driving severe asthma in women and the regulatory action of estradiol on activation of PI3K/Akt signaling pathway [35], suggests a possible gender specific function of mTOR inhibition.…”

Section: Asthma and Rhinitismentioning

confidence: 99%

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

Martinis

Sirufo

Suppa

et al. 2020

IJMS

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Allergies are rapidly worsening in recent decades, representing the most common immunological diseases. The mechanism of disorders such as asthma, rhinocongiuntivitis, urticaria, atopic dermatitis, food and drug allergies, and anaphylaxis still remain unclear and consequently treatments is mostly still symptomatic and aspecific while developments of new therapies are limited. A growing amount of data in the literature shows us how the prevalence of allergic diseases is different in both sexes and its changes over the course of life. Genes, hormones, environmental and immunological factors affect sex disparities associated with the development and control of allergic diseases, while they more rarely are considered and reported regarding their differences related to social, psychological, cultural, economic, and employment aspects. This review describes the available knowledge on the role of sex and gender in allergies in an attempt to improve the indispensable gender perspective whose potential is still underestimated while it represents a significant turning point in research and the clinic. It will offer insights to stimulate exploration of the many aspects still unknown in this relationship that could ameliorate the preventive, diagnostic, and therapeutic strategies in allergic diseases.

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“…Recent evidence has additionally demonstrated that the suppression of the malignant phenotype of OS cells by Aurora-B silencing might be achieved via autophagy-mediated activation of the mTOR/ULK1 signaling pathway. Thus, to further investigate the role of the mTOR/ULK1 pathway during Aurora-B silencing-induced autophagy, we investigated the expression of the autophagy-related protein p62 after treatment with MHY-1485, a well-known mTOR activator [ 25 ], or not, in Aurora-B-knockdown or scrambled OS cells. In the Aurora-B-knockdown OS cells, MHY-1485 treatment activated mTOR/ULK1 signaling and increased p62 levels.…”

Section: Resultsmentioning

confidence: 99%

Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway

Liu

Song

et al. 2020

Cancer Cell Int

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Background Autophagy plays an essential role in metastasis of malignancies. Although our studies showed that Aurora-B facilitate pulmonary metastasis in OS, the mechanism of Aurora-B kinase on autophagy and metastasis in OS has not been explored. Methods Clinical-pathological parameters and follow-up information was collected in OS patients. Immunohistochemical staining was performed to detect Aurora-B and LC3 protein in OS tissues. Short hairpin RNA transfection was used to silence Aurora-B in OS cells. Real-time quantitative PCR (RT-qPCR) was performed to detect Aurora-B mRNA expression in OS cells. Aurora-B and autophagy related protein were measured by Western blot. Transmission electron microscopy and laser scanning confocal microscopy were performed to observe the formation of autophagosomes and autolysosomes. Migratory and invasive ability of OS cells were measured by Wound healing and transwell assays. Orthotopic xenograft model was used to evaluate the effect of autophagy mediated by Aurora-B inhibition on pulmonary metastasis of OS. Results The elevated expression of Aurora-B protein in OS tissues negatively associated with the overall survival of OS patients. Further investigation has found that Aurora-B expression was negatively correlative with autophagy related protein LC3 in OS patient tissues. Knockdown Aurora-B stimulates autophagy and inhibits migratory and invasive ability of OS cells. Mechanistically, Aurora-B knockdown suppressed the mTOR/ULK1 signaling pathway and reactivation of the mTOR/ULK1 pathway decreased autophagy level. Furthermore, the inhibition effect of silencing Aurora-B on migration and invasion of OS was reversed by chloroquine and mTOR activator in vitro and vivo. Conclusions Our results suggest that silencing of Aurora-B stimulate autophagy via decreasing mTOR/ULK1 and result in inhibiting OS metastasis. Targeted Aurora-B/mTOR/ULK1 pathway may be a promising treatment strategy for OS patients.

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Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485

Cited by 23 publications

References 28 publications

Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter

Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway

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