Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0LDSGS)

• DOT Name: Nostrin (NOSTRIN)
• Synonyms: BM247 homolog; Nitric oxide synthase traffic inducer; Nitric oxide synthase trafficker; eNOS-trafficking inducer
• Gene Name: NOSTRIN
• Related Disease:
  Stroke
  Alcoholic hepatitis
  Liver cirrhosis
  Matthew-Wood syndrome
  Nasal polyp
  Pancreatic cancer
• UniProt ID: NOSTN_HUMAN
• PDB ID: 2YUN
• Pfam ID: PF00611 ; PF14604
• Sequence:
  MRDPLTDCPYNKVYKNLKEFSQNGENFCKQVTSVLQQRANLEISYAKGLQKLASKLSKAL
  QNTRKSCVSSAWAWASEGMKSTADLHQKLGKAIELEAIKPTYQVLNVQEKKRKSLDNEVE
  KTANLVISNWNQQIKAKKKLMVSTKKHEALFQLVESSKQSMTEKEKRKLLNKLTKSTEKL
  EKEDENYYQKNMAGYSTRLKWENTLENCYQSILELEKERIQLLCNNLNQYSQHISLFGQT
  LTTCHTQIHCAISKIDIEKDIQAVMEETAILSTENKSEFLLTDYFEEDPNSAMDKERRKS
  LLKPKLLRLQRDIEKASKDKEGLERMLKTYSSTSSFSDAKSQKDTAALMDENNLKLDLLE
  ANSYKLSSMLAELEQRPQPSHPCSNSIFRWREKEHTHSYVKISRPFLMKRLENIVSKASS
  GGQSNPGSSTPAPGAAQLSSRLCKALYSFQARQDDELNLEKGDIVIIHEKKEGGWWFGSL
  NGKKGHFPAAYVEELPSNAGNTATKA
• Function: Multivalent adapter protein which may decrease NOS3 activity by inducing its translocation away from the plasma membrane.
• Tissue Specificity: Expressed at highest levels in heart, kidney, placenta and lung, and at lowest levels in brain, thymus and spleen. Present in vascular endothelial cells and placenta. Over-expressed in placenta from women with pre-eclampsia (at protein level).
• Reactome Pathway: NOSTRIN mediated eNOS trafficking (R-HSA-203641)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stroke	DISX6UHX	Definitive	Biomarker	[1]
Alcoholic hepatitis	DISA7SH0	Strong	Genetic Variation	[2]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[2]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[3]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[4]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nostrin (NOSTRIN).	[5]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nostrin (NOSTRIN).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Nostrin (NOSTRIN).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Nostrin (NOSTRIN).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nostrin (NOSTRIN).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Nostrin (NOSTRIN).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nostrin (NOSTRIN).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nostrin (NOSTRIN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nostrin (NOSTRIN).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nostrin (NOSTRIN).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Nostrin (NOSTRIN).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nostrin (NOSTRIN).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Nostrin (NOSTRIN).	[16]

References

• [1] Altered gene expression in cerebral capillaries of stroke-prone spontaneously hypertensive rats.Brain Res. 2001 Aug 10;910(1-2):106-15. doi: 10.1016/s0006-8993(01)02670-1.
• [2] Increased gene and protein expression of the novel eNOS regulatory protein NOSTRIN and a variant in alcoholic hepatitis.Gastroenterology. 2007 Jun;132(7):2533-41. doi: 10.1053/j.gastro.2006.12.035. Epub 2006 Dec 20.
• [3] Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.Clin Cancer Res. 2016 Dec 15;22(24):5992-6001. doi: 10.1158/1078-0432.CCR-16-0511. Epub 2016 Jul 8.
• [4] Increased phosphorylation of eNOS in nasal polyps of chronic rhinosinusitis patients can be diminished by 1,8-cineol.Nitric Oxide. 2018 Aug 1;78:89-94. doi: 10.1016/j.niox.2018.06.002. Epub 2018 Jun 6.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.