Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUG1AOV)

• DOT Name: Ninjurin-2 (NINJ2)
• Synonyms: Nerve injury-induced protein 2
• Gene Name: NINJ2
• Related Disease:
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Colorectal carcinoma
  Dementia
  Glioma
  Multiple sclerosis
• UniProt ID: NINJ2_HUMAN
• PDB ID: 8SZB
• Pfam ID: PF04923
• Sequence:
  MESARENIDLQPGSSDPRSQPINLNHYATKKSVAESMLDVALFMSNAMRLKAVLEQGPSS
  HYYTTLVTLISLSLLLQVVIGVLLVVIARLNLNEVEKQWRLNQLNNAATILVFFTVVINV
  FITAFGAHKTGFLAARASRNPL
• Function: Effector of necroptotic and pyroptotic programmed cell death that mediates plasma membrane rupture (cytolysis). Acts downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively: oligomerizes in response to death stimuli and promotes plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane, leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response. Also acts as a homophilic transmembrane adhesion molecule involved in nerve regeneration. Promotes axonal growth.
• Tissue Specificity: Widely expressed. In adult, higher expression in the bone marrow and peripheral blood lymphocytes, medium in the lung, lymph node, thyroid, uterus, thymus, spleen, prostate and skeletal muscle, lower in the liver, placenta, brain, heart and kidney. In embryo, higher expression in the thymus, heart and liver, lower in the spleen, lung, brain and kidney.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ninjurin-2 (NINJ2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ninjurin-2 (NINJ2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ninjurin-2 (NINJ2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ninjurin-2 (NINJ2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ninjurin-2 (NINJ2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ninjurin-2 (NINJ2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ninjurin-2 (NINJ2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ninjurin-2 (NINJ2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ninjurin-2 (NINJ2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ninjurin-2 (NINJ2).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Ninjurin-2 (NINJ2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ninjurin-2 (NINJ2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ninjurin-2 (NINJ2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ninjurin-2 (NINJ2).	[18]

References

• [1] Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.PLoS One. 2011;6(6):e20573. doi: 10.1371/journal.pone.0020573. Epub 2011 Jun 6.
• [2] NINJ2- A novel regulator of endothelial inflammation and activation.Cell Signal. 2017 Jul;35:231-241. doi: 10.1016/j.cellsig.2017.04.011. Epub 2017 Apr 18.
• [3] Ninjurin 2 overexpression promotes human colorectal cancer cell growth in vitro and in vivo.Aging (Albany NY). 2019 Oct 9;11(19):8526-8541. doi: 10.18632/aging.102336. Epub 2019 Oct 9.
• [4] Ninjurin2 overexpression promotes glioma cell growth.Aging (Albany NY). 2019 Dec 2;11(23):11136-11147. doi: 10.18632/aging.102515. Epub 2019 Dec 2.
• [5] A single nucleotide polymorphism within Ninjurin 2 is associated with risk of multiple sclerosis.Metab Brain Dis. 2019 Oct;34(5):1415-1419. doi: 10.1007/s11011-019-00460-x. Epub 2019 Jul 10.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle. 2011 Mar;2(1):45-56. doi: 10.1007/s13539-011-0021-y. Epub 2011 Feb 26.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.