mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells

Soliman, Ghada A.; Abzalimov, Rinat R.; He, Ye

doi:10.3390/nu14153022

Cited by 3 publications

(1 citation statement)

References 45 publications

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“…We have previously shown that inhibition of the mTORC1 nutrient-sensing complex by Rapamycin and mTORC1/mTORC2 inhibition via either Torin-2 or RapaLink-1 have differential effects on the global untargeted metabolomics in vitro cell culture models [3]. In this proof-of-concept study, we leveraged the mummichog Python algorithm to analyze the high-dimension untargeted metabolomics data for modeling the biochemical pathways and metabolic networks, and predicting their functional activity using the XCMS Plus bioinformatics platform [4,5].…”

Section: Objectivesmentioning

confidence: 99%

Mechanistic Insights into the Metabolic Pathways Using High-Resolution Mass Spectrometry and Predictive Models in Pancreatic β-Cell Lines (β-TC-6)

Soliman,

He,

Abzalimov

2023

Iecn 2023

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Section: Objectivesmentioning

confidence: 99%

Mechanistic Insights into the Metabolic Pathways Using High-Resolution Mass Spectrometry and Predictive Models in Pancreatic β-Cell Lines (β-TC-6)

Soliman,

He,

Abzalimov

2023

Iecn 2023

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Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Hui

Guo

Zhu

et al. 2023

Preprint

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Acute myeloid leukemia (AML) is a disease of malignant proliferation of abnormally or poorly differentiated myeloid cells of the hematopoietic system. The clinical treatments of non-M3 AML are experiencing a lack of effective drugs. V8 is a newly synthesized derivative of the natural flavonoid wogonin, which belongs to the potential anticancer drug, and has shown significant antitumor activity in vitro and in vivo. In this study, we investigated the effects of V8 on AML cell lines and primary AML cells and the underlying mechanisms. The results showed that V8 inhibited the growth and induced the apoptosis of AML cell lines (ME-1, Kasumi-1, and U937) and primary AML cells in a concentration-dependent manner. Meanwhile, we revealed that V8-induced apoptosis was accompanied by mitochondrial injury, such as the reduction of mitochondrial membrane potential and ATP production, activation of endoplasmic reticulum stress (ERS) characterized by GRP78 and caspase-12 expression upregulation. Mechanism studies have shown that V8 induced mitochondrial injury and inhibited mitophagy via elevating the intracellular ROS level. In addition, V8 activated PERK-p-eIF2α-ATF4 and Ire1α-XBP1 pathways and induced apoptosis of AML cells via selectively activating CHOP. Correspondingly, the degree of apoptosis and expression of apoptosis-related proteins were alleviated after the elimination of cytoplasmic ROS with N-Acetyl-L-cysteine (NAC) and knocking out CHOP in the cells by transfection with CHOP shRNA, implicating that mitochondrial injury-triggered upregulation of ROS and CHOP played an important role in V8-induced apoptosis of AML cells. In primary AML cells-bearing NOD/SCID mice model and U937 cells-inoculating BALB/c nude mice xenografts transplantation tumor model, administration of V8 markedly prolonged survival time and inhibited the xenografts growth via CHOP-mediated ERS in vivo. In conclusion, our study provides a new insight into the mechanism of V8-induced apoptosis, suggesting the potential of V8 as a promising agent against AML.

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TORC1 Regulates Thermotolerance via Modulating Metabolic Rate and Antioxidant Capacity in Scallop Argopecten irradians irradians

Chu,

Liu,

Chang

et al. 2024

Antioxidants

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Target of rapamycin complex 1 (TORC1) is a key regulator of metabolism in eukaryotes across multiple pathways. Although TORC1 has been extensively studied in vertebrates and some invertebrates, research on this complex in scallops is limited. In this study, we identified the genes encoding TORC1 complex subunits in the scallop Argopecten irradians irradians through genome-wide in silico scanning. Five genes, including TOR, RAPTOR, LST8, DEPTOR, and PRAS40, that encode the subunits of TORC1 complex were identified in the bay scallop. We then conducted structural characterization and phylogenetic analysis of the A. i. irradians TORC1 (AiTORC1) subunits to determine their structural features and evolutionary relationships. Next, we analyzed the spatiotemporal expressions of AiTORC1-coding genes during various embryo/larvae developmental stages and across different tissues in healthy adult scallops. The results revealed stage- and tissue-specific expression patterns, suggesting diverse roles in development and growth. Furthermore, the regulation of AiTORC1-coding genes was examined in temperature-sensitive tissues (the mantle, gill, hemocyte, and heart) of bay scallops exposed to high-temperature (32 °C) stress over different durations (0 h, 6 h, 12 h, 24 h, 3 d, 6 d, and 10 d). The expression of AiTORC1-coding genes was predominantly suppressed in the hemocyte but was generally activated in the mantle, gill, and heart, indicating a tissue-specific response to heat stress. Finally, functional validation was performed using the TOR inhibitor rapamycin to suppress AiTORC1, leading to an enhanced catabolism, a decreased antioxidant capacity, and a significant reduction in thermotolerance in bay scallops. Collectively, this study elucidates the presence, structural features, evolutional relationships, expression profiles, and roles in antioxidant capacity and metabolism regulation of AiTORC1 in the bay scallop, providing a preliminary understanding of its versatile functions in response to high-temperature challenges in marine mollusks.

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mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells

Cited by 3 publications

References 45 publications

Mechanistic Insights into the Metabolic Pathways Using High-Resolution Mass Spectrometry and Predictive Models in Pancreatic β-Cell Lines (β-TC-6)

Mechanistic Insights into the Metabolic Pathways Using High-Resolution Mass Spectrometry and Predictive Models in Pancreatic β-Cell Lines (β-TC-6)

Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

TORC1 Regulates Thermotolerance via Modulating Metabolic Rate and Antioxidant Capacity in Scallop Argopecten irradians irradians

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