- |||||||||| Review, Journal: Therapeutic potential of the sphingosine kinase 1 inhibitor, PF-543. (Pubmed Central) - May 29, 2023
It is the rate-limiting enzyme of S1P production, and there is substantial evidence to support a very important role for sphingosine kinase in health and disease. This review is the first to summarize the role and mechanisms of PF-543 as an SPHK1 inhibitor in anticancer, antifibrotic, and anti-inflammatory processes, providing new therapeutic leads and ideas for future research and clinical trials.
- |||||||||| Journal: The SphK1/S1P axis regulates synaptic vesicle endocytosis via TRPC5 channels. (Pubmed Central) - May 15, 2023
The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathological conditions.
- |||||||||| S63845 / Servier, Novartis, HitGen
MCL-1 INHIBITION AFFECTS LIPIDOME WHICH MAY BE LINKED TO TUMOR IMMUNITY AND CANCER-RELATED INFLAMMATION IN ACUTE MYELOID LEUKEMIA () - May 12, 2023 - Abstract #EHA2023EHA_2589;
Additionally, the study highlights that S63845 has a distinct impact on the lipid profiles of different AML cell lines, indicating the potential of using lipidomic profiles asmarkers. Importantly, our study proposes that the increases in Cer levels in response to S63845 treatment may occur due to SM hydrolysis and may be linked to the anti-inflammatory effects of S63845 in AML cell lines, which deserve further investigation to fully understand the specific mechanisms.
- |||||||||| Journal: Discovery and design of dual inhibitors targeting Sphk1 and Sirt1. (Pubmed Central) - Apr 19, 2023
Among them, QST-LC03, QST-LD05, QST-LE03, and QST-LE04 have the better binding affinity than reference inhibitors. Moreover, the SwissADME and PASS platforms predict that 1, 3, QST-LC03, and QST-LE04 have further study value.
- |||||||||| fingolimod / Generic mfg.
UCHL1, A DEUBIQUITINATING ENZYME, AUGMENTS ENDOTHELIAL CELL BARRIER FUNCTION IN RADIATION- INDUCED LUNG INJURY (Regency Ballroom A/B (second floor)) - Apr 18, 2023 - Abstract #CSCTRMWAFMR2023CSCTR_MWAFMR_214;
Moreover, mice with a targeted deletion of SphK1 (SphK1- /-) exhibited marked RILI susceptibility and we confirmed significant RILI protection conferred by the sphingosine-1 phosphate (S1P) analog, (S)-FTY720-phosphonate (Tysiponate, Tys). Separately, we have also identified differential RILI responses mediated by the deubiquitinating enzyme, UCHL1 (ubiquitin carboxyl terminal esterase L1) and we have confirmed SphK1 ubiquitination is regulated by UCHL1.
- |||||||||| Understanding the involvement of sphingosine kinase-1 and two-pore channels in calcium signaling in T cells. (P582) (Exhibit Hall; Poster Board No. P582) - Apr 11, 2023 - Abstract #IMMUNOLOGY2023IMMUNOLOGY_586;
Therefore, we tested structural analogs of PF-543 and evaluated their ability to inhibit both SpK-1 and Ca2+ signals in DO.11.10 cells, a T cell hybridoma that possesses the T cell receptor (TCR). Thus, in addition to identifying novel targets for the development of Ca2+ signaling modulators and anticancer therapeutics, our results also reveal the contributions of SphK-1 and the TPCs in the NAADP-mediated Ca2+ signaling pathway in T cells.
- |||||||||| Yeliva (opaganib) / Apogee Biotech, RedHill
Sphingosine 1-phosphate / Acetyl CoA Carboxylase1 Axis regulates the Differentiation and Function of Tumor-associated Myeloid-Derived Suppressor Cells (P636) (Exhibit Hall; Poster Board No. P636) - Apr 11, 2023 - Abstract #IMMUNOLOGY2023IMMUNOLOGY_258;
Furthermore, in preclinical prostate and melanoma cancer models, the combination of PD1 antibody and SphK2 pharmacological inhibitor (ABC294640) dramatically reduced tumor growth and increased the survival of tumor bearing mice...Furthermore, investigations using deletion, overexpression, and site-directed mutagenesis demonstrated that ACC1 activity is necessary to preserve the immunogenic capacity of SphK2 KO MDSCs. This study highlights the clinical value of manipulating MDSC suppressive activity by targeting the S1P/ACC1 axis to boost T cell-mediated tumor control and highlights the crucial function that S1P plays as an immunoregulatory mediator in MDSCs.
- |||||||||| Journal, Metabolomic study: Therapeutic Mechanism of Baicalin in Experimental Colitis Analyzed Using Network Pharmacology and Metabolomics. (Pubmed Central) - Apr 7, 2023
Moreover, udp-glucose ceramide glucosyltransferase (UGCG), sphingomyelin synthase 1 (SGMS1), and sphingosine kinase (SPHK1) were predicted as sphingolipids-linked targets of baicalin against experimental colitis by integrative analysis. Based on these results, it implies that sphingolipid metabolism and sphingolipid signaling pathway might be acted as therapeutic mechanism for baicalin against experimental colitis.
- |||||||||| Journal: Beneficial Effects of Hordenine on a Model of Ulcerative Colitis. (Pubmed Central) - Mar 30, 2023
Using immunohistochemistry and western blotting, we demonstrated that hordenine reduced the expression of sphingosine kinase 1 (SPHK1), sphingosine-1-phosphate receptor 1 (S1PR1), and ras-related C3 botulinum toxin substrate 1 (Rac1), and it inhibited the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in colon tissues. Thus, hordenine appears to be effective in UC treatment owing to pharmacological mechanisms that favor mucosal healing and the inhibition of SPHK-1/S1PR1/STAT3 signaling.
- |||||||||| Modulation of Sphingolipid Metabolism and SARS-CoV-2 Infection in Lung (Walter E. Washington Convention Center, Area A, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_7007;
SARS-CoV-2 infection upregulates SK1 and increases the ratio of SK1 to CERS2 expression in lung tissues of COVID autopsies and COVID convalescents. This highlights alteration in sphingolipid rheostat in lung tissue during COVID-19, suggesting a potential contribution to the inflammation and tissue damage.
- |||||||||| fingolimod / Generic mfg.
UCHL1, a Deubiquitinating Enzyme, Augments Endothelial Cell Barrier Function in Radiation-induced Lung Injury (Walter E. Washington Convention Center, Area B, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_6908;
Collectively, our results yield new insights into mechanisms of sphingolipid signaling induced by radiation and support lung vascular-protective effects mediated by UCHL1. These findings may ultimately identify effective modulators of EC radiation responses that could also serve as effective therapeutic targets for RILI.
- |||||||||| Miostat (carbachol) / Novartis
Sphingosine 1 Phosphate Signaling Pathway Drives Female Asthma Susceptibility (Walter E. Washington Convention Center, Area A, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_4606;
Sex is a crucial determinant of sphingolipid metabolism and S1P's role in sex-related differences in airway structure and function. Thus, S1P signaling could represent a target for the treatment of asthma in a selected subset of patients selected based on their hormone levels.
- |||||||||| SPHK1 mediated regulation of antitumor immunity in ovarian cancer (Section 5; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_6684;
We are currently focusing on identifying the immune cells which are critical players in this process. We will further implement these findings in human immune cells for clinical benefits for ovarian cancer patients.
- |||||||||| Ceramide-dependent mitophagy leads to metabolic reprogramming in aging T-cells associated with reduced anti-tumor T-cell functions (Section 21; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_5147;
The fumarate supplementation also led to a decrease in ceramide-dependent mitophagy in the aging T-cells, indicating an interplay between ceramide-dependent mitophagy and fumarate metabolism. Overall, these studies help explain the mechanisms behind aging-related dysregulation of T-cell anti-tumor activity, which can be restored by inhibiting ceramide-dependent mitophagy by pharmacological and genetic tools or by reprogramming fumarate metabolism in aging T cells.
- |||||||||| EPB-53 prevents NASH-HCC transition via regulation of SPHK1-S1P-HIPPO signaling and immune modulation in a murine model (Section 22; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_2625;
In conclusion, targeting ASAH1 by Cer-IVA is an attractive strategy to inhibit S1P production, growth and stemness in PDAC cells. 1) Lack of FGF21 played a key role in lipid metabolic disorder and SPHK1-S1P-HIPPO signaling to promote NASH-HCC transition; 2) Lack of FGF21 rendered a TIM in NASH liver contributing to the NASH-HCC transition; 3) EPB?53 treatment can not only alleviate NASH, but also prevent NASH-HCC transition via lipid metabolic reprogramming, down-regulation of the SPHK1-S1P-HIPPO axis, and modulation of TIM.
- |||||||||| abiraterone acetate / Generic mfg.
Race- and ancestry-related metabolites and SNPs associated with response to secondary hormonal therapy in metastatic castration-resistant prostate cancer (Section 40; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_2260;
This study enrolled 50 self-reported Black and 50 self-reported White mCRPC patients, and such patients received abiraterone and prednisone until disease progression or adverse event...Evaluation of the function of these sphingolipids and SKIP in PCa cell drug response and aggressiveness are currently underway. These findings are furthering understanding of race- and ancestry-related biological factors that influence response to secondary hormonal therapy in mCRPC and have the potential to impact selection of patients for secondary hormonal therapy and to mitigate PCa disparity.
- |||||||||| Journal: CeO nanoparticles induce pulmonary fibrosis via activating S1P pathway as revealed by metabolomics. (Pubmed Central) - Mar 14, 2023
Collectively, our studies have identified the metabolomic changes in BEAS-2B cells exposed to CeO NPs with different aspect ratios and revealed the subtle changes in metabolic activities that traditional approaches might have missed. More importantly, we have discovered a previously unknown molecular mechanism underlying CeO NP-induced lung fibrosis with different aspect ratios, shedding new insights on the environmental hazard potential of CeO NPs.
- |||||||||| Journal: Sphingosine kinase 2 regulates insulin receptor trafficking in hepatocytes. (Pubmed Central) - Mar 4, 2023
Thus, our results show that SphK2 is able to regulate InsR trafficking. These findings suggest that SphK2 may impinge on hepatic insulin signaling by regulating InsR trafficking, providing further mechanistic evidence that SphK2 could serve as a potential intervention target against insulin resistance and T2D (type 2 diabetes).
- |||||||||| S. epidermidis increases contact sensitization inflammation through the S1P receptor 2 () - Mar 4, 2023 - Abstract #ISID2023ISID_1057;
These results confirm that S1PR2 in the epidermis is essential for tight junction recovery, and S.epidermidis (SE) can block Filaggrin recovery through S1PR2 pathways. Our results suggest that SE worsens ACD when S1PR2 is present in the epidermis but reduces it when S1PR2 is absent, supporting the hypothesis that SE increases contact sensitization inflammation through the S1PR2 receptor.
- |||||||||| Journal: Hydrogen sulfide alleviates ischemia induced liver injury by repressing the SPHK1/S1P pathway. (Pubmed Central) - Feb 23, 2023
Overall, HS effectively protected against I/R induced liver injury, decreased the inflammatory responses, and attenuated apoptosis of hepatocyte via inhibiting the ER stress response. These findings demonstrated that pre-treatment of HS protected against I/R induced liver injury by repressing the SPHK1/S1P pathway via inhibition of ER stress, suggesting an effective therapeutic method for the treatment of I/R induced liver injury.
- |||||||||| Biological analysis of new PROTACs for downregulation of sphingosine kinase 1 (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_12335;
Each PROTAC consists of an E3 ligase binder, a sphingosine kinase 1 (sk1) inhibitor, and a linker of varying structure and length. In quantitative assays, our PROTACs exhibit a hook effect as expected due to their chimeric nature and our PROTACs have shown to be effective at slowing cell growth at concentrations as low as 20 nM, much lower than the inhibitor alone.
- |||||||||| Synthesis and effectiveness of PROTACs targeting SphK1 (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_12261;
Our results also show the presence of the Hook effect, where too high a dosage will lower PROTAC potency, due to the chimeric nature of PROTACs. Our PROTACs are effective at lower concentrations when compared to the inhibitor alone because of their catalytic reactivity inherent to the PROTAC mechanism.
- |||||||||| Downregulating cellular sphingosine kinase 1 (SK1) concentrations in cancer models via a PROTAC approach (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_2814;
In this report, we describe the synthesis of new PROTACs for SK1 with various linker lengths and identities between the SK1 inhibitor and the E3 ligase inhibitor. The effectiveness of our new PROTACS was then measured against various cancer cell lines and western blot analysis was used to verify the change in cellular protein levels
- |||||||||| metformin / Generic mfg.
Review, Journal, Metastases: Targeting lipid metabolism in metastatic prostate cancer. (Pubmed Central) - Feb 7, 2023
Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.
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