Anti-aging drug D/S for targeting senescent cells in tissue micro-environment and application of anti-aging drug D/S

A technology of senescent cells and drugs, applied in drug combinations, medical preparations containing active ingredients, antidote, etc., can solve problems such as limited application, non-unique activation targets, applicability, accuracy, and actual effect limitations.

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

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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

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  • Anti-aging drug D/S for targeting senescent cells in tissue micro-environment and application of anti-aging drug D/S
  • Anti-aging drug D/S for targeting senescent cells in tissue micro-environment and application of anti-aging drug D/S
  • Anti-aging drug D/S for targeting senescent cells in tissue micro-environment and application of anti-aging drug D/S

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preparation example Construction

[0109] The present invention has no particular limitation on the preparation method of the interfering RNA molecule, including but not limited to: chemical synthesis method, in vitro transcription method and the like. The interfering RNA can be delivered into cells by using appropriate transfection reagents, or can also be delivered into cells by various techniques known in the art.

[0110] As another option of the present invention, the CRISPR / Cas9 system can be used for targeted gene editing, thereby knocking out the ABL, PTGS2 or BCL2A1 gene in the targeted disease region. Common methods for knocking out ABL, PTGS2 or BCL2A1 genes include: co-transferring sgRNA or nucleic acid capable of forming the sgRNA, Cas9 mRNA or nucleic acid capable of forming the Cas9 mRNA into the targeted region or targeted cells. After the target site is determined, known methods can be used to introduce sgRNA and Cas9 into the cells.

Embodiment 1

[0112] Example 1. Chemotherapeutic drugs induce senescence of human stromal cells and present typical senescence-related secretion phenotypes

[0113] 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 (10% FBS) medium, and BLEO was added to a final concentration of 50 μg / ml, and the whole transcriptome was sequenced by RNA-Seq on the 7th day after treatment.

[0114] 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.

[0115]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, CSF2, CCL2...

Embodiment 2

[0118] Example 2. Kinetic study of anti-aging drug candidate dasatinib and SIRT1 activator on cell survival under in vitro conditions

[0119] 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 condition...

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Abstract

The invention provides an anti-aging drug D/S for targeting senescent cells in a tissue micro-environment and application of the anti-aging drug D/S. Combined application of dasatinib and SRT2104 is adopted, and extremely excellent effects of reduction or removal of the senescent cells in the body are achieved, so that the drug is applied to removal damaged cells which are obtained after chemotherapy or radiation treatment and other damaged cells in the tissue micro-environment, and is also applied to elimination of cells which age naturally with ages, and the survival time of the body is prolonged.

Description

technical field [0001] The invention belongs to the field of pharmacy, and more specifically, the invention relates to an anti-aging drug D / S with the activity of targeting senescent cells in tissue microenvironment and its application. Background technique [0002] Senescent cells increase with age in most organs and tissues; in clinical settings, they also appear in organs associated with many chronic diseases and after chemotherapy and radiation. Cellular senescence, the process by which cells lose function (including the ability to divide and replicate) but remain resistant to death, has been shown to drive several age-related diseases such as osteoporosis, osteoarthritis, atherosclerosis and idiopathic pulmonary fibrosis, etc. [0003] 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 ...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/5377A61K45/00A61P39/00
CPCA61K31/506A61K31/5377A61K45/00A61P39/00A61K2300/00
Inventor 孙宇
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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