This is a Phase I, open-label, dose-escalation and dose-expansion study of NOX66 given rectally, in cohorts of patients with metastatic soft tissue sarcoma (STS) who have not been exposed to anthracycline therapy, using a fixed dose-escalation schema every 21 days to establish the maximum tolerated dose (MTD) of the combination of NOX66 and doxorubicin.

Start Date11 Feb 2022

Sponsor / Collaborator

Noxopharm Ltd.

EUCTR2021-001917-35-HU / Unknown statusPhase 1/2

A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors

Start Date25 Oct 2021

Sponsor / Collaborator

Noxopharm Ltd.

100 Clinical Results associated with SPHK1 x S1PRs x SPHK2

100 Translational Medicine associated with SPHK1 x S1PRs x SPHK2

0 Patents (Medical) associated with SPHK1 x S1PRs x SPHK2

Literatures (Medical) associated with SPHK1 x S1PRs x SPHK2

10 Aug 2023·Journal of ethnopharmacology

Study on the action mechanism of Buyang Huanwu Decoction against ischemic stroke based on S1P/S1PR1/PI3K/Akt signaling pathway.

Article

Author: Nie, Cong ; Liu, Wanyi ; Zhou, Xin ; Pei, Die ; Zhang, Yingfeng ; Huang, Jieyi ; Zhu, Lixia ; Zeng, Keqi

ETHNOPHARMACOLOGICAL RELEVANCEIschemic stroke is a common and frequent clinical disease. Recent studies have demonstrated that sphingolipid plays an important role in the pathological process of ischemic stroke. PI3K-Akt is a classic protective signaling pathway of cerebral ischemic injury. After acting on the S1P receptor, S1P can activate the downstream PI3K/Akt signaling pathway and play an anti-cerebral ischemia role. Buyang Huanwu Decoction (BHD) is a traditional Chinese medicine formula used to treat ischemic stroke. However, the mechanisms of BHD on ischemic stroke remain unclear based on S1P/S1PR1/PI3K/Akt signaling pathway.AIM OF THE STUDYThe present study is intended to investigate the action mechanism of BHD on ischemic stroke based on the S1P/S1PR1/PI3K/Akt signaling pathway from multiple perspectives.MATERIALS AND METHODSThe BHD lyophilized product was prepared by vacuum freeze-drying method, of which the chemical composition was determined by UPLC-Q-TOF/MS. The mouse permanent middle cerebral artery occlusion (pMCAO) model was established by the suture-occluded method. Male KM mice were randomly divided into seven groups: sham group, model group, FTY720 (positive control) group, BHD group, BHD + W146 (selective S1PR1 inhibitor) group, SEW2871 (selective S1PR1 agonist) group, and Calycosin group. Each group was administered continuously for 14 days and evaluated with modified neurological severity score (mNSS) and cerebral infarct volume on the 1st, 4th, 7th, and 14th days. The SphK1, SphK2, S1PR1, PI3K, Akt, and p-Akt protein in the prefrontal lobe, hippocampus, and striatum was quantified by Western blot and immunohistochemical (IHC) experiment respectively. The qRT-PCR method was employed to evaluate SphK1, SphK2, and S1PR1 mRNA expression in the above tissue.RESULTSBHD and Calycosin both effectively improved mNSS scores with smaller infarct volumes. The SphK1 level in the prefrontal lobe, hippocampus, and striatum of mice in the BHD group was significantly lower, and SphK2, PI3K, and p-Akt in the hippocampus and striatum were significantly higher than those in the model group. BHD significantly decreased SphK1 mRNA expression in the prefrontal lobe, hippocampus, and striatum, and significantly up-regulated SphK2 mRNA and S1PR1 mRNA expression. Additionally, SphK1 protein expression levels of the prefrontal lobe, hippocampus, and striatum in the BHD group was significantly lower than model group, and SphK2, S1PR1, PI3K, Akt, and p-Akt protein expressions levels were increased obviously. Furthermore, SEW2871 can increase S1PR1 and Akt expression, and up-regulate SphK2 and S1PR1 mRNA expression. The effect of BHD on the expression of S1P/S1PR1/PI3K/Akt signaling pathway-related proteins and mRNA were weakened by BHD + W146.CONCLUSIONBHD and Calycosin significantly improved the symptoms of neurological deficits in pMCAO mice, reduced the cerebral infarction volume, up-regulated SphK2 and S1PR1 mRNA levels, enhanced SphK2, S1PR1, PI3K, Akt, p-Akt protein expression of the prefrontal lobe, hippocampus and striatum, and down-regulated SphK1 mRNA and protein expression, which may be helpful to clarify the mechanism of BHD through S1P/S1PR1/PI3K/Akt signaling pathway to protect against cerebral ischemic injury.

01 Aug 2022·The FASEB Journal

Intestinal aberrant sphingolipid metabolism shaped‐gut microbiome and bile acids metabolome in the development of hepatic steatosis

Article

Author: Miao, Rong‐Rong ; Zhan, Sheng ; Qu, Xian‐Jun ; Cui, Shu‐Xiang

Conjugated bile acids (CBAs) play major roles in hepatic gene regulation via nuclear S1P-inhibited histone deacetylase (HDACs). Gut microbiota modifies bile acid pool to generate CBAs and then CBAs returned to liver to regulate hepatic genes, fatty liver, and non-alcoholic fatty liver disease (NAFLD). However, it is not yet known how the gut microbiota was modified under the environment of inflammatory bowel disease (IBD). Here, we revealed that aberrant intestinal sphingosine kinases (SphKs), a major risk factor of IBD, modified gut microbiota by increasing the proportions of Firmicutes and Verrucomicrobia, which were associated with the increase in CBAs. When exposed to a high-fat diet (HFD), sphingosine kinases 2 knockout (SphK2KO) mice developed more severity of intestinal inflammation and hepatic steatosis than their wild-type (WT) littermates. Due to knockdown of nuclear SphK2, Sphk2KO mice exhibited an increase in sphingosine kinases 1 (SphK1) and sphingosine-1-phosphate (S1P) in intestinal epithelial cells. Therefore, the microbiota was modified in the environment of the SphK1/S1P-induced IBD. 16S rDNA amplicon sequencing of cecal contents indicated an increase of Firmicutes and Verrucomicrobia. Ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) measured an increase in CBAs, including taurocholic acid (TCA), taurodeoxycholic acid (TDCA), and glycocholic acid (GCA), in cecal contents and liver tissues of Sphk2KO mice. These CBAs accumulated in the liver promoted hepatic steatosis through downregulating the acetylation of H3K9, H3K14, H3K18 and H3K27 due to the CBAs-S1PR2-nuclear SphK2-S1P signaling pathway was blocked in HFD-SphK2KO mice. In summary, intestinal aberrant sphingolipid metabolism developed hepatic steatosis through the increase in CBAs associated with an increase in Firmicutes and Verrucomicrobia.

01 Apr 2022·PlacentaQ3 · MEDICINE

Downregulation of miR-33a/b and miR-181a contributes to recurrent pregnancy loss by upregulating S1PR1 and repressing regulatory T cell differentiation

Q3 · MEDICINE

Article

Author: Xiang, Yungai ; Yu, Guo ; Mao, Genhong ; Zhao, Dongmei ; Wang, Meng ; Geng, Xujing ; Tan, Li

INTRODUCTIONSuccessful pregnancy in humans requires adequate maternal-fetal immune tolerance. During regulatory T (Treg) cells play a key role. Sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) signaling represses Treg cell differentiation, but whether this relates to the process of recurrent pregnancy loss is still unclear.METHODSTreg cells in the placenta were examined using flow cytometry. The expression of sphingosine kinase-1 and -2(SPHK1 and SPHK2), two key kinases controlling S1P production, was detected in placenta samples from 36 patients with recurrent pregnancy loss (RPL) and 40 control participants using immunoblotting. The level of sphingosine-1-phosphate receptor-1 (S1PR1) in placental T cells was examined using RT-qPCR and immunoblotting. Cell surface S1PR1 levels were detected using flow cytometry. The interactions between miRNAs and S1PR1 mRNA were predicted using bioinformatics tools and were confirmed by dual luciferase assay and immunoblotting.RESULTSRPL patients had fewer Treg cells (p = 0.034) in the placenta, especially TIM3+ Treg cells (p = 0.0076). S1PR1 protein levels were significantly increased in placental T cells of patients with RPL (p = 0.0065). MiR-33a, miR-33b, and miR-181a were reduced in the placenta from patients with RPL, which were identified to repress S1PR1 expression by targeting the 3'UTR. Knockdown of miR-33a, miR-33b and miR-181a in human naïve T cells inhibits Treg cell differentiation by upregulating S1PR1 in vitro.DISCUSSIONThis study, for the first time, successfully constructed the correlation between dysregulated miRNAs in placenta and RPL, which partially unveiled the etiology of RPL and provided a therapeutic potential for RPL treatment.

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