Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3G4AR)

• DOT Name: Spexin (SPX)
• Synonyms: NPQ; Neuropeptide Q; Spexin hormone
• Gene Name: SPX
• Related Disease:
  Anorexia nervosa cachexia
  Arteriosclerosis
  Atherosclerosis
  Autism
  Eating disorder
  Fatty liver disease
  Neuralgia
  Non-alcoholic fatty liver disease
  Chronic obstructive pulmonary disease
  Type-1 diabetes
  Anxiety
  Anxiety disorder
  Cardiovascular disease
  Cystic fibrosis
  Non-insulin dependent diabetes
  Prediabetes syndrome
• UniProt ID: SPXN_HUMAN
• PDB ID: 7XJL
• Pfam ID: PF15171
• Sequence:
  MKGLRSLAATTLALFLVFVFLGNSSCAPQRLLERRNWTPQAMLYLKGAQGRRFISDQSRR
  KDLSDRPLPERRSPNPQLLTIPEAATILLASLQKSPEDEEKNFDQTRFLEDSLLNW
• Function: Plays a role as a central modulator of cardiovascular and renal function and nociception. Also plays a role in energy metabolism and storage. Inhibits adrenocortical cell proliferation with minor stimulation on corticosteroid release; [Spexin-1]: Acts as a ligand for galanin receptors GALR2 and GALR3. Intracerebroventricular administration of the peptide induces an increase in arterial blood pressure, a decrease in both heart rate and renal excretion and delayed natriuresis. Intraventricular administration of the peptide induces antinociceptive activity. Also induces contraction of muscarinic-like stomach smooth muscles. Intraperitoneal administration of the peptide induces a reduction in food consumption and body weight. Inhibits long chain fatty acid uptake into adipocytes; [Spexin-2]: Intracerebroventricular administration of the peptide induces a decrease in heart rate, but no change in arterial pressure, and an increase in urine flow rate. Intraventricular administration of the peptide induces antinociceptive activity.
• Tissue Specificity: Expressed in the type I glomic cells within the carotid body (at protein level). Expressed predominantly in pancreas, testis, kidney, brain and placenta. Expressed in submucosal layer of esophagus and stomach fundus.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Eating disorder	DISVGXN0	Strong	Biomarker	[1]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[4]
Neuralgia	DISWO58J	Strong	Biomarker	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[4]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[6]
Type-1 diabetes	DIS7HLUB	Disputed	Altered Expression	[7]
Anxiety	DISIJDBA	Limited	Altered Expression	[8]
Anxiety disorder	DISBI2BT	Limited	Altered Expression	[8]
Cardiovascular disease	DIS2IQDX	Limited	Biomarker	[9]
Cystic fibrosis	DIS2OK1Q	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[11]
Prediabetes syndrome	DISH2I53	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Spexin (SPX).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Spexin (SPX).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Spexin (SPX).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Spexin (SPX).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Spexin (SPX).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Spexin (SPX).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Spexin (SPX).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Spexin (SPX).	[20]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Spexin (SPX).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Spexin (SPX).	[21]

References

• [1] Longitudinal study on novel neuropeptides phoenixin, spexin and kisspeptin in adolescent inpatients with anorexia nervosa - association with psychiatric symptoms.Nutr Neurosci. 2021 Nov;24(11):896-906. doi: 10.1080/1028415X.2019.1692494. Epub 2019 Nov 18.
• [2] Spexin Levels Are Associated with Metabolic Syndrome Components.Dis Markers. 2018 Sep 4;2018:1679690. doi: 10.1155/2018/1679690. eCollection 2018.
• [3] Brief Report: Relationship between non-verbal IQ and gender in autism.J Autism Dev Disord. 2009 Jan;39(1):188-93. doi: 10.1007/s10803-008-0612-4. Epub 2008 Jul 2.
• [4] Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin.Semin Liver Dis. 2016 Sep;36(4):360-372. doi: 10.1055/s-0036-1597248. Epub 2016 Dec 20.
• [5] LncRNA NONRATT021972 Was Associated with Neuropathic Pain Scoring in Patients with Type 2 Diabetes.Behav Neurol. 2017;2017:2941297. doi: 10.1155/2017/2941297. Epub 2017 Aug 8.
• [6] Cigarette smoke modifies and inactivates SPLUNC1, leading to airway dehydration.FASEB J. 2018 Jun 11;32(12):fj201800345R. doi: 10.1096/fj.201800345R. Online ahead of print.
• [7] Decreased Spexin Levels in Patients with Type 1 and Type 2 Diabetes.Med Princ Pract. 2018;27(6):549-554. doi: 10.1159/000493482. Epub 2018 Sep 5.
• [8] Overexpression of Spexin 1 in the Dorsal Habenula Reduces Anxiety in Zebrafish.Front Neural Circuits. 2019 Aug 14;13:53. doi: 10.3389/fncir.2019.00053. eCollection 2019.
• [9] Spexin protects cardiomyocytes from hypoxia-induced metabolic and mitochondrial dysfunction.Naunyn Schmiedebergs Arch Pharmacol. 2020 Jan;393(1):25-33. doi: 10.1007/s00210-019-01708-0. Epub 2019 Aug 8.
• [10] SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum.J Cyst Fibros. 2019 Mar;18(2):244-250. doi: 10.1016/j.jcf.2018.06.002. Epub 2018 Jun 20.
• [11] Effect of obesity and type 2 diabetes, and glucose ingestion on circulating spexin concentration in adolescents.Pediatr Diabetes. 2018 Mar;19(2):212-216. doi: 10.1111/pedi.12549. Epub 2017 Jun 19.
• [12] Favorable Changes in Fasting Glucose in a 6-month Self-Monitored Lifestyle Modification Programme Inversely Affects Spexin Levels in Females with Prediabetes.Sci Rep. 2019 Jul 1;9(1):9454. doi: 10.1038/s41598-019-46006-0.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] 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.
• [21] 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.