Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLRZ1EU)

• DOT Name: Ninjurin-1 (NINJ1)
• Synonyms: hNINJ1; Nerve injury-induced protein 1
• Gene Name: NINJ1
• Related Disease:
  Allergic contact dermatitis
  Hereditary sensory and autonomic neuropathy type 1
  Advanced cancer
  Aortic valve stenosis
  Bone disease
  Endometriosis
  Neoplasm
  Obesity
  Pneumonia
  Pneumonitis
  Pulmonary fibrosis
  Alopecia
  Adult glioblastoma
  Glioblastoma multiforme
  T-lymphoblastic lymphoma
  Bailey-Bloch congenital myopathy
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Prune belly syndrome
  Stroke
  Type-1/2 diabetes
• UniProt ID: NINJ1_HUMAN
• PDB ID: 8CQR; 8SZA
• Pfam ID: PF04923
• Sequence:
  MDSGTEEYELNGGLPPGTPGSPDASPARWGWRHGPINVNHYASKKSAAESMLDIALLMAN
  ASQLKAVVEQGPSFAFYVPLVVLISISLVLQIGVGVLLIFLVKYDLNNPAKHAKLDFLNN
  LATGLVFIIVVVNIFITAFGVQKPLMDMAPQQ
• Function: [Ninjurin-1]: 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. Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS. Involved in leukocyte migration during inflammation by promoting transendothelial migration of macrophages via homotypic binding. Promotes the migration of monocytes across the brain endothelium to central nervous system inflammatory lesions. Also acts as a homophilic transmembrane adhesion molecule involved in various processes such as axonal growth, cell chemotaxis and angiogenesis. Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells. Plays a role in nerve regeneration by promoting maturation of Schwann cells. Acts as a regulator of angiogenesis. Promotes the formation of new vessels by mediating the interaction between capillary pericyte cells and endothelial cells. Promotes osteoclasts development by enhancing the survival of prefusion osteoclasts. Also involved in striated muscle growth and differentiation; [Secreted ninjurin-1]: Secreted form generated by cleavage, which has chemotactic activity. Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis.
• Tissue Specificity: Widely expressed in both adult and embryonic tissues, primarily those of epithelial origin.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic contact dermatitis	DISFFVF9	Definitive	Biomarker	[1]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Aortic valve stenosis	DISW7AQ9	Strong	Biomarker	[4]
Bone disease	DISE1F82	Strong	Altered Expression	[5]
Endometriosis	DISX1AG8	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Pneumonia	DIS8EF3M	Strong	Biomarker	[8]
Pneumonitis	DIS88E0K	Strong	Biomarker	[8]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[9]
Alopecia	DIS37HU4	moderate	Biomarker	[10]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[11]
T-lymphoblastic lymphoma	DISGFZXW	Disputed	Biomarker	[3]
Bailey-Bloch congenital myopathy	DISGFJL6	Limited	Biomarker	[12]
Lung cancer	DISCM4YA	Limited	Biomarker	[13]
Lung carcinoma	DISTR26C	Limited	Biomarker	[13]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[14]
Prune belly syndrome	DISBIBMN	Limited	Genetic Variation	[12]
Stroke	DISX6UHX	Limited	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

2 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-1 (NINJ1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ninjurin-1 (NINJ1).	[34]

25 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-1 (NINJ1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ninjurin-1 (NINJ1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Ninjurin-1 (NINJ1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ninjurin-1 (NINJ1).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ninjurin-1 (NINJ1).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ninjurin-1 (NINJ1).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Ninjurin-1 (NINJ1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ninjurin-1 (NINJ1).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ninjurin-1 (NINJ1).	[18]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ninjurin-1 (NINJ1).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Ninjurin-1 (NINJ1).	[17]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ninjurin-1 (NINJ1).	[26]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ninjurin-1 (NINJ1).	[27]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Ninjurin-1 (NINJ1).	[28]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Ninjurin-1 (NINJ1).	[29]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Ninjurin-1 (NINJ1).	[30]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Ninjurin-1 (NINJ1).	[17]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Ninjurin-1 (NINJ1).	[17]
Morphine	DMRMS0L	Approved	Morphine increases the expression of Ninjurin-1 (NINJ1).	[31]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ninjurin-1 (NINJ1).	[32]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Ninjurin-1 (NINJ1).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ninjurin-1 (NINJ1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ninjurin-1 (NINJ1).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ninjurin-1 (NINJ1).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ninjurin-1 (NINJ1).	[37]

References

• [1] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [2] Exclusion of the ninjurin gene as a candidate for hereditary sensory neuropathies type I and type II.Am J Med Genet. 1999 Apr 23;83(5):409-10.
• [3] Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner.Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11500-11505. doi: 10.1073/pnas.1711814114. Epub 2017 Oct 9.
• [4] Ninjurin1 regulates striated muscle growth and differentiation.PLoS One. 2019 May 15;14(5):e0216987. doi: 10.1371/journal.pone.0216987. eCollection 2019.
• [5] Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts.Exp Mol Med. 2019 Jan 16;51(1):1-16. doi: 10.1038/s12276-018-0201-3.
• [6] Expression of Nerve Injury-Induced Protein1 (Ninj1) in Endometriosis.Reprod Sci. 2019 Aug;26(8):1105-1110. doi: 10.1177/1933719118806395. Epub 2018 Oct 16.
• [7] Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.Nat Genet. 2013 May;45(5):513-7. doi: 10.1038/ng.2607. Epub 2013 Apr 7.
• [8] Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation.Am J Respir Cell Mol Biol. 2015 Nov;53(5):656-63. doi: 10.1165/rcmb.2014-0354OC.
• [9] Ninjurin1 Plays a Crucial Role in Pulmonary Fibrosis by Promoting Interaction between Macrophages and Alveolar Epithelial Cells.Sci Rep. 2018 Dec 3;8(1):17542. doi: 10.1038/s41598-018-35997-x.
• [10] Disruption of Ninjurin1 Leads to Repetitive and Anxiety-Like Behaviors in Mice.Mol Neurobiol. 2017 Nov;54(9):7353-7368. doi: 10.1007/s12035-016-0207-6. Epub 2016 Nov 5.
• [11] MicroRNA-139-3p suppresses growth and metastasis of glioblastoma via inhibition of NIN1/RPNI2 binding protein 1 homolog.Eur Rev Med Pharmacol Sci. 2019 May;23(10):4264-4274. doi: 10.26355/eurrev_201905_17931.
• [12] Neuroprotective and Anti-inflammatory Effects of a Dodecamer Peptide Harboring Ninjurin 1 Cell Adhesion Motif in the Postischemic Brain.Mol Neurobiol. 2018 Jul;55(7):6094-6111. doi: 10.1007/s12035-017-0810-1. Epub 2017 Nov 14.
• [13] Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway.Int J Cancer. 2016 Jul 15;139(2):383-95. doi: 10.1002/ijc.30021. Epub 2016 Feb 16.
• [14] Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis.Brain Res Mol Brain Res. 2003 Nov 26;119(2):170-83. doi: 10.1016/j.molbrainres.2003.09.008.
• [15] Functional blocking of Ninjurin1 as a strategy for protecting endothelial cells in diabetes mellitus.Clin Sci (Lond). 2018 Jan 19;132(2):213-229. doi: 10.1042/CS20171273. Print 2018 Jan 31.
• [16] 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.
• [17] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [18] Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis. Life Sci. 2003 Aug 15;73(13):1705-19. doi: 10.1016/s0024-3205(03)00515-0.
• [19] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [20] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [23] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [24] 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.
• [25] 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.
• [26] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [29] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [30] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [31] Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim Biophys Acta. 2009 Aug;1790(8):793-9. doi: 10.1016/j.bbagen.2009.04.011. Epub 2009 May 3.
• [32] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [33] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [34] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [35] 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.
• [36] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.