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Estrogen is a key hormone that regulates female development and reproduction, and at the same time has an important regulatory effect on energy metabolism.
The anticancer drug tamoxifen is very effective in the treatment of estrogen receptor-positive breast cancer, but it is accompanied by side effects such as hot flashes, fatigue and bone changes.
Although the negative effects of these chemotherapy have severely impaired the quality of life of patients, the mechanism of its action is poorly understood.
Recently, Dr.
Zhi Zhang (first author of the paper) from the Stephanie Correa team at the University of California, Los Angeles, etc.
published an article entitled Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice in eLife magazine.
Through tissue specificity Gene knockout and single-cell sequencing revealed that the estrogen receptor alpha (ERα) located in the hypothalamus is a key target that mediates tamoxifen's metabolic side effects such as hot flashes.
Selective knockout of ERa in the mouse hypothalamus completely blocked the increase in thermogenesis, decreased activity and bone mass caused by tamoxifen treatment.
The researchers first simulated the side effects of tamoxifen administration in mice, such as the disturbance of body temperature regulation.
They found that subcutaneous injection of tamoxifen at a simulated clinical dose for 4 weeks can significantly reduce the core body temperature of mice, accompanied by a reduction in brown fat heat production and an increase in tail heat dissipation.
In addition, tamoxifen treatment reduced the amount of activity in the mice but increased the bone density of the mice.
Tamoxifen inhibits the proliferation of cancer cells by acting on the cell’s estrogen receptor alpha (ERα).
Because ERα is widely present in the central hypothalamus and has a close regulatory effect on body temperature, activity and bone quality, the researchers speculated that tamoxifen These metabolic side effects caused by Xifen may act on the central hypothalamus.Through the droplet sorting single-cell sequencing technology, the researchers found that under the action of tamoxifen, the transcriptome of various types of cells in the hypothalamus has undergone significant changes, of which neuron and ependymal cell gene expression changes are the most intense.
After further analysis of neuronal cells, the researchers identified the cellular metabolic pathways and the corresponding molecular targets that are more prominently affected by tamoxifen, providing a theoretical basis for improving tamoxifen's drug treatment.
Excerpted from the popular science report "All in the head" [1] Next, in order to study the role of hypothalamus ERα in the influence of tamoxifen on normal physiological and metabolic functions, the researchers targeted the mouse hypothalamus to knock out ERα, and again Observe the effects of tamoxifen on the above physiological indicators and hypothalamic transcriptome in mice.
Interestingly, conditional knockout of ERa almost reversed the mode of gene transcription regulation of tamoxifen on hypothalamic neurons and ependymal cells.
That is, genes that were originally up-regulated by tamoxifen were down-regulated by tamoxifen after ERα was knocked out; otherwise, genes that were down-regulated were changed to up-regulation.
At the same time, the physiological changes caused by tamoxifen, such as decreased body temperature, decreased activity, and changes in bone quality, were no longer affected in knockout mice.
These results prove the leading role of hypothalamic ERα in the influence of tamoxifen on normal physiological changes.
This study reveals the neural molecular mechanism of the side effects of the chemotherapy drug tamoxifen, and provides new ideas for the design of new drugs without side effects (such as estrogen receptor modulators that do not pass the blood-brain barrier).
The research was strongly supported by Yang Xia's laboratory and research team.
Original link: https://elifesciences.
org/articles/63333 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Offenders must be investigated.
The anticancer drug tamoxifen is very effective in the treatment of estrogen receptor-positive breast cancer, but it is accompanied by side effects such as hot flashes, fatigue and bone changes.
Although the negative effects of these chemotherapy have severely impaired the quality of life of patients, the mechanism of its action is poorly understood.
Recently, Dr.
Zhi Zhang (first author of the paper) from the Stephanie Correa team at the University of California, Los Angeles, etc.
published an article entitled Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice in eLife magazine.
Through tissue specificity Gene knockout and single-cell sequencing revealed that the estrogen receptor alpha (ERα) located in the hypothalamus is a key target that mediates tamoxifen's metabolic side effects such as hot flashes.
Selective knockout of ERa in the mouse hypothalamus completely blocked the increase in thermogenesis, decreased activity and bone mass caused by tamoxifen treatment.
The researchers first simulated the side effects of tamoxifen administration in mice, such as the disturbance of body temperature regulation.
They found that subcutaneous injection of tamoxifen at a simulated clinical dose for 4 weeks can significantly reduce the core body temperature of mice, accompanied by a reduction in brown fat heat production and an increase in tail heat dissipation.
In addition, tamoxifen treatment reduced the amount of activity in the mice but increased the bone density of the mice.
Tamoxifen inhibits the proliferation of cancer cells by acting on the cell’s estrogen receptor alpha (ERα).
Because ERα is widely present in the central hypothalamus and has a close regulatory effect on body temperature, activity and bone quality, the researchers speculated that tamoxifen These metabolic side effects caused by Xifen may act on the central hypothalamus.Through the droplet sorting single-cell sequencing technology, the researchers found that under the action of tamoxifen, the transcriptome of various types of cells in the hypothalamus has undergone significant changes, of which neuron and ependymal cell gene expression changes are the most intense.
After further analysis of neuronal cells, the researchers identified the cellular metabolic pathways and the corresponding molecular targets that are more prominently affected by tamoxifen, providing a theoretical basis for improving tamoxifen's drug treatment.
Excerpted from the popular science report "All in the head" [1] Next, in order to study the role of hypothalamus ERα in the influence of tamoxifen on normal physiological and metabolic functions, the researchers targeted the mouse hypothalamus to knock out ERα, and again Observe the effects of tamoxifen on the above physiological indicators and hypothalamic transcriptome in mice.
Interestingly, conditional knockout of ERa almost reversed the mode of gene transcription regulation of tamoxifen on hypothalamic neurons and ependymal cells.
That is, genes that were originally up-regulated by tamoxifen were down-regulated by tamoxifen after ERα was knocked out; otherwise, genes that were down-regulated were changed to up-regulation.
At the same time, the physiological changes caused by tamoxifen, such as decreased body temperature, decreased activity, and changes in bone quality, were no longer affected in knockout mice.
These results prove the leading role of hypothalamic ERα in the influence of tamoxifen on normal physiological changes.
This study reveals the neural molecular mechanism of the side effects of the chemotherapy drug tamoxifen, and provides new ideas for the design of new drugs without side effects (such as estrogen receptor modulators that do not pass the blood-brain barrier).
The research was strongly supported by Yang Xia's laboratory and research team.
Original link: https://elifesciences.
org/articles/63333 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Offenders must be investigated.
