更新于：2024-11-01

5-LOX x ALOX12

更新于：2024-11-01

基本信息

关联

项与 5-LOX x ALOX12 相关的药物

SRI-11226

靶点

5-LOX x ALOX12

作用机制

5-LOX抑制剂 [+1]

在研机构-

原研机构

SRI International

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

SRI-31291

靶点

12/15-LOX x 5-LOX x ALOX12

作用机制

12/15-LOX抑制剂 [+2]

在研机构-

原研机构

Western University of Health Sciences

在研适应症-

非在研适应症

创伤性脑损伤

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 5-LOX x ALOX12 相关的临床结果

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100 项与 5-LOX x ALOX12 相关的转化医学

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0 项与 5-LOX x ALOX12 相关的专利（医药）

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216

项与 5-LOX x ALOX12 相关的文献（医药）

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Eicosanoid biosynthesizing enzymes in Prototheria

Article

作者: Heydeck, Dagmar ; Kakularam, Kumar R. ; Stehling, Sabine ; Rothe, Michael ; Gündem, Eda ; Kakularam, Kumar R ; Kuhn, Hartmut

Eicosanoids and related compounds are pleiotropic lipid mediators, which play a role in cell differentiation and in the pathogenesis of various diseases. The biosynthesis of these lipids has extensively been studied in highly developed mammals including humans but little is known about the formation of these mediators in more ancient Prototheria. We searched the genomes of two extant prototherian species (platypus, short-beaked echidna) for genes encoding for lipoxygenase- (ALOX) and prostaglandin synthase-isoforms (PTGS) and detected intact single copy genes for ALOX5, ALOX12, ALOX12B, ALOXE3, PTGS1 and PTGS2. Moreover, we identified two copies of ALOX15B genes (ALOX15B-1 and ALOX15B-2) but in echidna the ALOX15B-2 gene was structurally corrupted. Interestingly, in the two genomes ALOX15 genes were lacking. For functional characterization we expressed the prototherian ALOX15B isoforms and compared important enzyme characteristics of the wildtype proteins and of relevant enzyme mutants with those of human and mouse ALOX15B. Here we observed that the prototherian ALOX15B isoforms exhibit the same reaction specificity as their human ortholog. Mutagenesis of the Triad determinants did not alter the reaction specificity of the prototherian enzymes but modification of the Jisaka determinants murinized the catalytic properties. These data indicate that Prototheria exhibit an active eicosanoid metabolism. They express functional ALOX15B orthologs but lack ALOX15 genes. These observations and the previous findings that ALOX15 orthologs rarely occur in non-mammalian vertebrates such as fish and birds suggest that ALOX15 orthologs were introduced during Prototheria-Metatheria transition via an ALOX15B gene duplication and subsequent divergent enzyme evolution.

2024-04-01·Journal of Cellular and Molecular Medicine

SBFI26 induces triple‐negative breast cancer cells ferroptosis via lipid peroxidation

Article

作者: Liu, Mei ; Zhang, Yiyuan ; Liu, Wei ; Ke, Youqiang ; Liang, Li ; Chen, Tangcong ; He, Gang ; Feng, Yanjiao ; Yin, Xiaojing ; Yan, Jun ; Qu, Shaokui ; Zeng, Yue ; Huang, Lifen

AbstractSBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK‐8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T‐SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time‐ and dose‐dependent, with a more significant inhibitory effect on MDA‐MB‐231 cells. Fer‐1, GSH and Vitamin C attenuated the effects but not erastin. RNA‐Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T‐SOD, total glutathione (T‐GSH), and GSH levels.SBFI26 dose‐dependently up‐regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.

2023-11-01·Cancer Prevention Research

Polymorphisms in Cyclooxygenase, Lipoxygenase, and TP53 Genes Predict Colorectal Polyp Risk Reduction by Aspirin in the seAFOod Polyp Prevention Trial

Article

作者: Downing, Amy ; Race, Amanda D ; Harland, Mark ; Minihane, Anne Marie ; Davies, John R ; Brown, Louise C ; Rees, Colin J ; Hull, Mark A ; Mell, Tracey ; Loadman, Paul M ; Williams, Elizabeth A ; Saleh, Rasha N M ; Fuller, Harriett

AbstractAspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 SNPs in oxylipin metabolism genes such as cyclooxygenase (PTGS) and lipoxygenase (ALOX), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53–0.90); q = 0.06], rs2745557 (PTGS2) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41–0.88); q = 0.06], rs7090328 (ALOX5) rare homozygotes [IRR 0.27 (0.11–0.64); q = 0.05], rs2073438 (ALOX12) common homozygotes [IRR, 0.57 (0.41–0.80); q = 0.05], and rs104522 (TP53) rare homozygotes [IRR, 0.37 (0.17–0.79); q = 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin.Prevention Relevance:Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most.