Anti-aging medicine D/A targeting at aging cells in tissue microenvironment and application of anti-aging medicine D/A

A technology of senescent cells and drugs, applied in the field of biomedicine, can solve problems such as limitations of applicability and practical effects, and inability to remove

Active Publication Date: 2020-03-31
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a large number of follow-up studies internationally indicate that this method needs more testing before it can be formally used in humans
In addition to the fact that these two drugs may bring some unknown side effects during long-term treatment, their applicability and actual effect cannot be effectively eliminated because they cannot effectively remove stromal cell groups such as fibroblasts that occupy a large number in the tissue microenvironment. restricted

Method used

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  • Anti-aging medicine D/A targeting at aging cells in tissue microenvironment and application of anti-aging medicine D/A
  • Anti-aging medicine D/A targeting at aging cells in tissue microenvironment and application of anti-aging medicine D/A
  • Anti-aging medicine D/A targeting at aging cells in tissue microenvironment and application of anti-aging medicine D/A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1. Chemotherapeutic drugs induce senescence of human stromal cells and present typical senescence-related secretion phenotypes

[0104] The present inventors treated the primary human prostate stromal cell line PSC27 with the genotoxic chemotherapeutic drug bleomycin (BLEO). PSC27 cells were cultured in DMEM (containing 10% FBS) medium, and BLEO was added to a final concentration of 50 μg / ml. The whole transcriptome was sequenced by RNA-Seq on the 7th day after treatment.

[0105] Definition of proliferating (PRE) and senescent (SEN) cells: For cultured cells, they were defined by SA-β-Gal and BrdU staining techniques, senescent cells were positive for SA-β-Gal, and proliferative cells were positive for BrdU.

[0106] The results showed that senescent (SEN) cells had profoundly altered gene expression profiles compared to proliferating state (PRE) cells. In the list of up-regulated genes, a large number of SASP typical exocrine factors appeared, such as IL8, CS...

Embodiment 2

[0109] Example 2. Kinetic study of anti-aging drug candidates dasatinib and aspirin on cell survival under in vitro conditions

[0110] First, the inventors investigated the effects of selective knockout of some genes on stromal cells. Combined with individual genes that are up-regulated after PSC27 aging and related to anti-apoptosis, such as PTGS2, BCL2A1, and SERPINB2, the inventors knocked out ABL, EFNB1, EFNB3, PTGS2, BCL2A1, SERPINB2, and ATPLite using shRNA. The results showed that only the deletion of ABL, PTGS2, and BCL2A1 could significantly reduce the survival rate of senescent stromal cells (PSC27, human embryonic lung fibroblast WI38) ( Figure 5 , Figure 6 ). Likewise, crystal violet staining confirmed that PTGS2, BCL2A1 had significant effects on survival in these two cell lines ( Figure 7 , Figure 8 ). Since it affects both senescent (SEN) cells and proliferating (PRE) cells, it may affect the microenvironment under normal physiological conditions.

[...

Embodiment 3

[0121] Example 3. A large number of senescent cells in the tissue microenvironment caused by radiotherapy can be removed by the combination of dasatinib and aspirin

[0122] The inventors treated wild-type mice with γ-rays (10 Gy) and performed in-depth analysis 3 months later. Dasatinib was taken 1 month after radiation treatment, and the dosage was: dasatinib 5mg / kg, aspirin 50mg / kg.

[0123] The results of histochemical staining confirmed that about 57% of the cells in the tissue microenvironment had p16 INK4a Positive, but significantly reduced (approximately 60% reduction) under the condition of Da / A combination. At the same time, compared with the control (placebo group), p21 in mouse tissue CIP1 The proportion of positive cells also decreased significantly ( Figure 17 ).

[0124] The present inventors performed SA-β-Gal staining analysis on tissue sections, and the evaluation results confirmed that ionizing radiation itself can significantly increase the proportion...

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Abstract

The invention provides an anti-aging medicine D/A targeting at aging cells in a tissue microenvironment and application of the anti-aging medicine D/A. Dasatinib is combined with aspirin, and a very excellent effect in reducing or eliminating aging cells of a body can be achieved, so that the medicine can be used for eliminating damaged cells such as damaged cells in the tissue microenvironment after chemotherapy or radiation therapy, and can be also used for eliminating cells aged naturally along with ages, and thus the living time of the body can be prolonged.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically, the invention relates to anti-aging drug D / A based on targeting senescent cells in tissue microenvironment and its application. Background technique [0002] Senescent cells persist under in vivo conditions and have long-lasting effects on surrounding cells. This is mainly because senescent cells tend to develop a so-called senescence-associated secretoryphenotype (SASP), which allows these cells to continuously secrete large amounts of pro-inflammatory and microenvironment-remodeling molecules. Transcriptional analysis found that, like cancer cells, senescent cells have enhanced expression of factors involved in a "pro-survival network" that help them resist apoptosis or other forms of programmed cell death. [0003] Cell senescence usually manifests as nuclear membrane infolding, chromatin condensation, lipofuscin accumulation, cell volume increase, nucleus enlargement, increa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/616A61K31/506A61P39/00
CPCA61K31/616A61K31/506A61P39/00A61K2300/00
Inventor 孙宇
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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