hydrocotarnine

Hydrocotarnine is a Cbl inhibitor, and results in inflammasome-mediated IL-18 secretion in colitis. Hydrocotarnine increases expression of GLUT1 and cellular glucose uptake in glycolytic metabolism. Hydrocotarnine acts as an agent that provides analgesic effect in cancer research[1][2][3].

Signaling Pathways >> Metabolic Enzyme/Protease >> E1/E2/E3 Enzyme

Research Areas >> Inflammation/Immunology

Research Areas >> Metabolic Disease

Research Areas >> Neurological Disease

Cbl[1][2]

Hydrocotarnine is an analgesic agent (CRIN-2), with the patent ID of WO2011160016A2[1]. Hydrocotarnine (10 μM; 1 h) elevates the secretion of IL-1β and IL-18, and (0.1-10 μM; 1 h) increases the global level of tyrosine-phosphorylated proteins in THP-1 cells[1]. Hydrocotarnine (50 μM; 0-100 min) increases the glycolytic capacity and glycolytic reserve capacity in THP-1-derived macrophages[2]. Hydrocotarnine (50 μM; 16 h) inhibits Cbl and increases the total GLUT1 protein in THP-1-derived macrophages[2]. Hydrocotarnine is known to enhance the analgesic effect of opioids, and alleviates cancer pain[3]. Western Blot Analysis[1] Cell Line: THP-1 cells Concentration: 0.1, 1, 10 μM Incubation Time: 1 hour Result: Induced p-Pyk2 loss and increased the level of tyrosine-phosphorylated proteins in a dose-dependent manner.

Hydrocotarnine (10 mg/kg/d; i.p.; 9 d) shows inhibitory effect on Cbl and results in increasing IL-18 levels, indicating that NLRP3 inflammasome activation is enhanced in mice[1]. Hydrocotarnine (10 mg/kg/d; i.p.; 9 d) protects mice from DSS-induced colitis, with low scores of pathological evaluation of inflammation, epithelial defects, and crypt atrophy[1]. Animal Model: DSS-induced colitis model in C57BL/6 mice (6-9 weeks old)[1] Dosage: 10 mg/kg Administration: Intraperitoneal injection; once daily; 9 days while 2.5% DSS treatment began on day 1 and ended on day 7 Result: Significantly attenuated the weight loss of DSS-induced colitis mice compared to PBS-treated control mice, indicating that decreasing negative regulation of the NLRP3 inflammasome activation could attenuate colitis in an animal model.

[1]. Chung IC, et al. Src-family kinase-Cbl axis negatively regulates NLRP3 inflammasome activation. Cell Death Dis. 2018 Oct 31;9(11):1109.

[2]. Lin HC, et al. Cbl Negatively Regulates NLRP3 Inflammasome Activation through GLUT1-Dependent Glycolysis Inhibition. Int J Mol Sci. 2020 Jul 19;21(14):5104.

[3]. Kim KU, et al. DITMD-induced mitotic defects and apoptosis in tumor cells by blocking the polo-box domain-dependent functions of polo-like kinase 1. Eur J Pharmacol. 2019 Mar 15;847:113-122.

DATA ITEMS CITED :

2

MOLECULAR FORMULA :

C12-H15-N-O3

MOLECULAR WEIGHT :

221.28

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

160 mg/kg

TOXIC EFFECTS :

Behavioral - tremor Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

PHARAT Pharmazie. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1946- Volume(issue)/page/year: 15,111,1960

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

100 mg/kg

TOXIC EFFECTS :

Behavioral - tremor Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

PHARAT Pharmazie. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1946- Volume(issue)/page/year: 15,111,1960