A Novel, LAT/Lck Double Deficient T Cell Subline J.CaM1.7 for Combined Analysis of Early TCR Signaling

Vico-Barranco, Inmaculada; Arbulo-Echevarria, Mikel M.; Serrano-García, Isabel; Pérez-Linaza, Alba; Miranda-Sayago, José Maria; Miazek, Arkadiusz; Narbona-Sánchez, Isaac; Aguado, Enrique

doi:10.3390/cells10020343

Cited by 4 publications

(1 citation statement)

References 63 publications

(104 reference statements)

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“…LCK, a cytoplasmic tyrosine kinase expressed in T cells and natural killer cells, is a necessary step to activate T cell. Therefore, selective inhibition of LCK can produce immunosuppressive effects [38]. As an important pathway for extracellular signal transduction into the nucleus, MAPK cascade plays an important role in cell proliferation, differentiation and apoptosis [39].…”

Section: Discussionmentioning

confidence: 99%

Potential mechanism of action of Jing Fang Bai Du San in the treatment of COVID-19 using docking and network pharmacology

Li¹,

Zhang²,

Bao³

et al. 2022

Int. J. Med. Sci.

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Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severely infects people and has rapidly spread worldwide. JingFangBaiDu San (JFBDS) has been used to treat prevalent epidemic pathogens, common cold, headache, cough due to lung-cold, and other symptoms; however, its treatment for COVID-19 is unknown. Molecular docking and network pharmacology were applied to obtain ingredient-protein structures and the herb-ingredient-disease target network model, respectively, to explore the potential mechanism of JFBDS in COVID-19 treatment. Network pharmacology analysis showed that acacetin, wogonin, and isorhamnetin were the main active ingredients of JFBDS, and EGFR, PIK3CA, LCK, MAPK1, MAPK3, MAPK8, STAT3, TNF, IL2, and RELA were speculated to be crucial therapeutic targets. Moreover, the Toll-like receptors, HIF-1, PIK3K/AKT, MAPK, NF-κB and NOD-like receptor signaling pathways were important for JFBDS in COVID-19 treatment. Molecular docking analysis indicated that ingredients of JFBDS could bind to angiotensin converting enzyme II, spike protein, and chymotrypsin like protease (3CLpro), which inhibits virus entry and replication in host cells. This study provides a new perspective for understanding potential therapeutic effects and mechanisms of JFBDS in COVID-19 and may facilitate its clinical application.

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Section: Discussionmentioning

confidence: 99%

Potential mechanism of action of Jing Fang Bai Du San in the treatment of COVID-19 using docking and network pharmacology

Li¹,

Zhang²,

Bao³

et al. 2022

Int. J. Med. Sci.

View full text Add to dashboard Cite

show abstract

Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia

Laukkanen

Veloso

Yan

et al. 2022

Blood

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Relapse and refractory T cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 inhibitors and the general tyrosine kinase-inhibitor, dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.

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Integrated bioinformatics and in silico approaches reveal the biological targets and molecular mechanisms of 1,25-dihydroxyvitamin D against COVID-19 and diabetes mellitus

Zeng

Tang

et al. 2022

Front. Nutr.

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Coronavirus disease 2019 (COVID-19) and diabetes mellitus (DM) are two major diseases threatening human health. The susceptibility of DM patients to COVID-19 and their worse outcomes have forced us to explore efficient routes to combat COVID-19/DM. As the most active form of Vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) has been shown a beneficial effect in the treatment of COVID-19/DM. However, the anti-COVID-19/DM mechanisms of 1,25(OH)2D remain unclear. In this study, an approach combining network pharmacology and molecular docking was performed to reveal the potential hub target genes and underlying mechanisms of 1,25(OH)2D in the treatment of COVID-19/DM. The hub targets and interaction pathways related to 1,25(OH)2D were identified by integrating the key 1,25(OH)2D-target-signaling pathway-COVID-19/DM networks. Fifteen hub targets of 1,25(OH)2D against COVID-19DM were determined, including EGFR, PIK3R1, PIK3CA, STAT3, MAPK1, ESR1, HSP90AA1, LCK, MTOR, IGF1, AR, NFKB1, PIK3CB, PTPN1, and MAPK14. An enrichment analysis of the hub targets further revealed that the effect of 1,25(OH)2D against COVID-19/DM involved multiple biological processes, cellular components, molecular functions and biological signaling pathways. Molecular docking disclosed that 1,25(OH)2D docked nicely with the hub target proteins, including EGFR, PIK3R1, and PIK3CA. These findings suggested that the potential mechanisms of 1,25(OH)2D against COVID-19/DM may be related to multiple biological targets and biological signaling pathways.

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A Novel, LAT/Lck Double Deficient T Cell Subline J.CaM1.7 for Combined Analysis of Early TCR Signaling

Cited by 4 publications

References 63 publications

Potential mechanism of action of Jing Fang Bai Du San in the treatment of COVID-19 using docking and network pharmacology

Potential mechanism of action of Jing Fang Bai Du San in the treatment of COVID-19 using docking and network pharmacology

Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia

Integrated bioinformatics and in silico approaches reveal the biological targets and molecular mechanisms of 1,25-dihydroxyvitamin D against COVID-19 and diabetes mellitus

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