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CN-121971488-A - Application of inorganic arsenic compound or metabolite thereof in preparation of NRF2 sustained high-expression medicament

CN121971488ACN 121971488 ACN121971488 ACN 121971488ACN-121971488-A

Abstract

The invention belongs to the field of tumors, and relates to application of inorganic arsenic compounds or metabolites thereof in preparation of medicines for continuously and highly expressing NRF2, wherein after HaCaT and MIHA cells are exposed at different concentrations DMMTA Ⅴ , the expression level of total protein of cell KEAP1 is reduced, the expression level of total protein of NRF2 is increased, and further, after purified KEAP1 protein is treated by 10.0 mu M DMMTA Ⅴ , the free sulfhydryl of KEPA1 protein is obviously reduced. The above results indicate that arsenic metabolite DMMTA Ⅴ binds to the key cysteine residues of KEAP1 protein, resulting in its conformational change, loss of function and reduced stability, thereby releasing NRF2 and activating antioxidant pathways. In summary, inorganic arsenic compounds and metabolites may bind to KEAP1 protein thiol, mediating sustained high expression of NRF 2.

Inventors

  • ZHAO CHEN
  • AN YAN
  • YANG QIANLEI
  • LU HUI

Assignees

  • 苏州大学

Dates

Publication Date
20260505
Application Date
20260213

Claims (10)

  1. 1. The application of inorganic arsenic compound or metabolite thereof in preparing NRF2 sustained high-expression medicament.
  2. 2. The use according to claim 1, wherein the inorganic arsenic compound is DMA III .
  3. 3. The use according to claim 1, wherein the metabolite is DMMTA Ⅴ .
  4. 4. The use according to claim 2, wherein the DMA III contamination concentration is 0.05-10 μm.
  5. 5. The use according to claim 2, wherein the DMA III exposure time is 20-28 h.
  6. 6. The use according to claim 3, wherein DMMTA Ⅴ is at a contamination concentration of 0.05 to 10 μm.
  7. 7. The use according to claim 3, wherein DMMTA Ⅴ exposure time is 20-28 h.
  8. 8. Use according to claim 1, characterized in that the inorganic arsenic compound or a metabolite thereof is used to activate the KEAP1-NRF2 pathway.
  9. 9. The use according to claim 1, wherein said NRF2 is continuously highly expressed as NRF2 nuclear in-rich.
  10. 10. Use according to claim 1, characterized in that the inorganic arsenic compound or a metabolite thereof is used for reducing free sulfhydryl groups.

Description

Application of inorganic arsenic compound or metabolite thereof in preparation of NRF2 sustained high-expression medicament Technical Field The invention belongs to the field of tumors, and relates to application of an inorganic arsenic compound or a metabolite thereof in preparation of an NRF2 sustained high-expression medicament. Background The diversity of arsenic metabolites determines the pleiotropic effects of arsenic toxicity, one of which is its subsequent impact on a variety of intracellular molecular targets. Arsenic compounds inhibit their physiological functions by specifically binding to sulfhydryl groups in proteins, an important mechanism for their toxic action. In recent years, research focuses on the interaction between different arsenic forms and proteins, and trivalent methylation arsenic metabolites MMA Ⅲ and DMA Ⅲ are found to have high affinity for cysteine residues and can form stable combination with various functional proteins such as hemoglobin, metallothionein and the like. Notably, the metabolic transformation mediated by the sulfur transferase family member Rhodanese further enriches the arsenic metabolic pathway, which can catalyze DMA III to DMMTA Ⅴ. Arsenic metabolites DMA III and DMMTA Ⅴ showed significantly lower half-inhibitory concentrations on HaCaT cells than inorganic arsenic, while cells treated with DMMTA Ⅴ detected sulfanilate formation. Sulfanyl sulfide is a class of compounds containing active sulfur atoms (e.g., polysulfides, persulfides) that modify the sulfhydryl groups of cysteine residues of proteins by thiolation to form disulfide bonds, thereby regulating protein function or cell signaling pathways. The IVR region of the connecting segment of KEAP1 is rich in cysteines and is a homologous zinc finger protein whose activity is dependent on cysteine residues. Arsenic, in particular trivalent arsenic, is readily bound to thiol-rich proteins. The continuous high-expression NRF2 up-regulates G6PD/NADK, and controls the cell redox steady-state unbalance caused by the increase of NADP synthesis, and the AS3MT mediated arsenic methylation metabolic process is enhanced, so that the malignant proliferation of the cells is promoted. However, why NRF2 is continuously expressed in high levels remains to be elucidated in further experiments. Disclosure of Invention In order to solve the technical problems, the invention provides application of inorganic arsenic compounds or metabolites thereof in preparing NRF2 sustained high-expression drugs, so as to regulate and control arsenic-induced cell malignant proliferation. The technical scheme provided by the invention is as follows: The application of inorganic arsenic compound or metabolite thereof in preparing NRF2 sustained high-expression medicament. Further, the inorganic arsenic compound is DMAIII. Further, the metabolite is DMMTAV. Furthermore, DMAIII is 0.05-10 mu M in contamination concentration. Furthermore, the DMAIII contamination time is 20-28 h. Furthermore, DMMTAV is 0.05-10 mu M in contamination concentration. Furthermore, the DMMTAV contamination time is 20-28 h. Further, the inorganic arsenic compound or a metabolite thereof is used to activate the KEAP1-NRF2 pathway. Further, the NRF2 is continuously and highly expressed as NRF2 is nuclear-in highly expressed. Further, the inorganic arsenic compound or a metabolite thereof is used for reducing free mercapto groups. Advantageous effects After the HaCaT cells and the MIHA cells are exposed at different concentrations DMMTA Ⅴ, the expression level of the total protein of the cell KEAP1 is reduced, the expression level of the total protein of the NRF2 is increased, and further, after the purified KEAP1 protein is treated by 10.0 mu M DMMTA Ⅴ, the free sulfhydryl of the KEPA1 protein is obviously reduced. The above results indicate that arsenic metabolite DMMTA Ⅴ binds to the key cysteine residues of KEAP1 protein, resulting in its conformational change, loss of function and reduced stability, thereby releasing NRF2 and activating antioxidant pathways. In summary, inorganic arsenic compounds and metabolites may bind to KEAP1 protein thiol, mediating sustained high expression of NRF 2. Drawings FIG. 1 shows the change in protein levels of NRF2 and KEAP1 after 24h exposure to HaCaT and MIHA cells at various concentrations of NaAsO 2. Note that (A, C) is the expression level of NRF2 and KEAP1 proteins of HaCaT and MIHA cells respectively, and (B, D) is the quantitative analysis result of the total NRF2 and KEAP1 proteins of HaCaT and MIHA cells respectively. * P <0.05 compared to the control group. FIG. 2 shows the variation of NRF2 and KEAP1 protein levels in the cytoplasmic nuclei of HaCaT and MIHA cells infected with NaAsO 2 at various concentrations for 24 h. Note that (A, C) is the expression level of proteins of HaCaT and MIHA cytosolic NRF2, KEAP1 protein and nuclear NRF2, respectively, and (B, D) is the quantitative analysis result of HaCaT and MIHA cytoso