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Sphingosine kinase 1 has distinct roles in the activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs) in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR-19b-3p.
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Low SPHL1 expression is associated with Huntington's disease.
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High SPHK1 expression is associated with pulmonary arterial hypertension.
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Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in Alzheimer's disease patients and in a transgenic mouse model.
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vascular transcriptome analysis shows that S1P pathway is critical in the regulation of vascular function in AngII-induced hypertension, although Sphk1 may have opposing roles in the regulation of vasoconstriction and endothelium-dependent vasorelaxation.
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these findings suggest that SphK1 may play a pivotal role in HER2-positive breast carcinogenesis
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The cell division gene PCNA was significantly overexpressed in SK2(-/-) cells, suggesting a cross regulation between sphingosine kinases and Ceramide glucosyltransferase.
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SphK1 expression regulates the early stage of colon carcinogenesis and tumor growth, thus inhibition of SphK1 may be an effective strategy for colon cancer chemoprevention.
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Studied role of microglial cells in inflammation via a Toll-like receptor 2 (TLR2)-->sphingosine kinase 1 (Sphk1)-->pro-inflammatory cytokine pathway in cerebral ischemia/reperfusion (I/R).
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SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors.
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These results suggest that SphK1 expression plays a pivotal role in the early stages of colon carcinogenesis
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the recruitment of Sphk1 to sphingosine-enriched endocytic vesicles and the generation of sphingosine-1-phosphate facilitate membrane trafficking along the endosomal pathway.
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SK1 activation is renoprotective via induction of autophagy in the fibrotic process
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donor islets from mice deficient in Sphk1 KO contain a reduced number of resident intraislet vascular endothelial cells. The main product of Sphk1, sphingosine-1-phosphate, controls the migration of intraislet endothelial cells in vitro. In vivo, Sphk1 knockout islets have an impaired ability to cure diabetes compared with wild-type controls.
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Sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis by stimulation of proliferation of cancer cells.
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These results highlight the importance of sphingosine and its conversion to sphingosine-1-phosphate by SphK1 in endocytic membrane trafficking.
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Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis.
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These findings suggest that the inhibitory effect of these plant extracts on the activation of AGEs/RAGE/SphK1 signaling pathway in db/db diabetic mice kidney is a novel mechanism by which they exert renoprotective effects in diabetic nephropathy.
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Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-kappaB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation.
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SphK1 dependent PKC-delta activation plays an important role in promoting NF-kappaB activation and inflammatory response in acute liver failure, and inhibition of PKC-delta activation might be a potential therapeutic strategy for this disease.
