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Introduction: ALDH2 catalyzes the production of acetate from alcohol in the brain, which is the main cause of neurotransmitter changes and behavioral effects in the brain caused by alcohol.
In our country’s wine culture has a long history, almost every festive meal, family and friends gatherings have two drinks.
It is well known that behavioral disorders and other drunken-related behaviors occur after drinking, but the overall situation of the core mechanism of alcohol metabolism is still unclear.
Alcohol, a psychoactive substance that is often abused, causes significant pathology in the entire medical field.
Unlike opioids, nicotine and other psychoactive chemicals, ethanol does not bind to any specific targets or receptors in the brain.
Ethanol metabolites can produce psychoactive effects, which last longer than ethanol in the human body.
Xianjiu liver is the main organ for alcohol detoxification.
Most of the alcohol is first metabolized by the alcohol dehydrogenase (ALDH) in the liver to acetaldehyde, then acetaldehyde dehydrogenase type 2 (ALDH2) is metabolized to acetic acid, and finally eliminated from the body.
Metabolites enter the brain from the liver through the blood and cause movement disorders.
Due to the very low content of various alcohol-metabolizing enzymes in the brain, coupled with the lack of precise and specific research tools, the role of the brain in alcohol metabolism has been ignored.
In addition, people lack understanding of the role of acetic acid (commonly known as acetic acid), a lower metabolite of alcohol.
For a long time, acetic acid has been designated as the non-toxic and harmless metabolic end product of alcohol.
Recently, the team of Professor Zhang Ye from the Department of Anesthesiology and Perioperative Medicine of the Second Affiliated Hospital of Anhui Medical University and Professor Zhang Li from the Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health jointly published a study on Nature Metabolism, which revealed Alcohol causes brain function and behavioral disorders.
ALDH2 catalyzes the production of acetate from alcohol in the brain, which is the main reason for alcohol-induced neurotransmitter changes and behavioral effects in the brain.The research was also selected as the cover paper of the current issue.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z In this study, the researchers first used quantitative PCR to detect the expression of ALDH2 mRNA in different brain regions (Figure 1a) .
Among the 5 tested areas, the expression level of ALDH2 mRNA was the most abundant in the cerebellum and the least in the prefrontal cortex (PFC).
In the detection of ALDH2 enzymatic activity, three different cerebellar subregions showed the highest level of ALDH2 enzymatic activity, which was also the least in PFC.
Subsequently, the researchers used RNAscope technology to perform RNA in situ hybridization.
At low magnification, strong ALDH2 signals were detected in all lobes of the mouse cerebellar sagittal slice (Figure 1b).
The expression of ALDH2 in astrocytes in the cerebellum.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z.
Due to the lack of methods to distinguish between central and peripheral ALDH2 mediated effects, the alcohol metabolism pathway in the brain has an impact on human behavior.
Not yet clear.
To overcome this problem, the researchers constructed ALDH2 knockout mouse models of liver (Aldh2Hep−/−) or astrocytes (Aldh2Gfap−/−).
The results showed that in Aldh2Gfap−/− mice, acetic acid And GABA (an important inhibitory neurotransmitter) did not increase, which also indicates that both acetate and GABA are derived from the ALDH2 enzyme activity in astrocytes.Schematic diagram of the metabolic pathway of ethanol to acetic acid in the liver and brain.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z GABA levels, and through the GABAergic mechanism to mediate alcohol-induced dyskinesia, which proves that there is a connection between ALDH2 in astrocytes and GABA synthesis and its signaling pathways.
It was also observed that in 3 human and 11 mouse brain samples, ALDH2 can be expressed in cerebellar astrocytes.
As we all know, the cerebellum is the brain area that controls balance and motor coordination.
When ALDH2 is removed from the cerebellar astrocytes, the mice are resistant to dyskinesia caused by drinking alcohol.
Generally, drinking alcohol increases the content of acetate and GABA in the brain; however, when ALDH2 is removed from astrocytes, this increase can be prevented.
In contrast, removing ALDH2 from the liver will not affect the levels of acetate or GABA in the brain.
These findings indicate that the ability of acetic acid produced in the brain and liver to affect motor function is different.
The results of the entire study overturned previous cognition, indicating that acetic acid is an alcohol metabolite related to dyskinesia.
Astrocytes in the cerebellum metabolize ethanol to acetic acid through ALDH2 enzyme.
Acetic acid metabolites increase GABA levels in the cerebellum, and induce the body's drunken balance and motor coordination disorders through the GABAergic mechanism.
Although previous scientific studies believed that the liver produces ALDH2, this study found for the first time that ALDH2 is also present in astrocytes in the brains of mice and humans.
The first author of the article and Dr.
Jin Shiyun from the Department of Anesthesia and Perioperative Medicine of the Second Affiliated Hospital of Anhui Medical University analyzed that, overall, the ALDH2 enzyme has different roles in the liver and brain.
More than 90% of alcohol is metabolized in the liver after drinking, but the products of liver metabolism have little effect on the inhibitory neurotransmitter GABA in the brain.
The metabolism of alcohol in the brain directly causes the increase of GABA, thereby inhibiting brain function, which also suggests that the astrocyte ALDH2 in the brain is the main mechanism of alcohol directly regulating related behavioral damage to the brain.
At the same time, it is recommended to further study the role of this enzyme in humans.
This study suggests that astrocyte ALDH2 may be a useful target for the treatment of alcoholism.
It can be used to regulate the expression of astrocyte ALDH2 to help relieve alcohol, abstain from alcohol, and prevent and treat alcohol-induced brain damage and degeneration.
At the same time, it opens up a new direction for studying the related mechanisms of drunken behavior, and can also provide references for the pathogenesis and treatment of neurological diseases such as dementia (Alzheimer's syndrome).
In fact, the research results are particularly important for Asians, especially East Asians.
In 2020, a joint research team from several Japanese institutions such as the University of Tokyo and the National Cancer Institute in Japan published a study in Science Advances, which pointed out that ALDH2 gene mutations are related to redness on the back of drinking, and people who blush after drinking are at risk of gastric cancer.
Bigger.
In this cross-ethnic study, researchers sequenced the genomes of 531 gastric cancer patients (319 Asian and 212 non-Asian) and divided them into 6 groups based on the mutation characteristics of the tissue samples, Signature 1, 3, 6, 15, 16, 17.
The analysis found that in the Signature 16 group, 70% of patients carried ALDH2 gene mutations, and more than 90% of the patients were Asians, and the average alcohol consumption of patients in this group was not high.
This also means that patients with ALDH2 gene mutations, even if they only drink a small amount of alcohol, will have a significantly increased risk of gastric cancer.
Signature1,3,6,15,16,17 gene mutation analysis.
Defined lifestyle and germline factors predispose Asian populations to gastric cancer.
DOI: 10.
1126/sciadv.
aav9778helloguma and the distribution of ALDH2 genes in different populations around the world is significantly different.
According to researchers from the National Institute of Alcoholism and Alcoholism in the United States and the Kurihama Alcohol Research Center in Japan, about one-third of East Asians lack ALDH2, and about 40% of Asians have genetic defects in alcohol metabolism.
People who carry an ALDH2*2 gene, the ALDH enzyme activity is only 6% of the normal, while the two genes are all ALDH2*2, the ALDH enzyme activity is almost zero, which is the legendary "pour a cup.
"
The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.
doi: 10.
1371/journal.
pmed.
1000050 Among them, the highest is the Han nationality in Guangdong, which is as high as 31%, which is rare in European and American populations.
ALDH2 * Geographical distribution of 504Lys allele frequency.
The gray scale indicates the allele distribution frequency, and the hollow red triangle indicates the position of the overall sample.
The surrounding black lines indicate the frequency boundaries of the 0.
12 and 0.
24 distributions.
Refined Geographic Distribution of the Oriental ALDH2*504Lys(nee487Lys) Variant.
doi:10.
1111/j.
1469-1809.
2009.
00517.
x In summary, for a long time, a large amount of data has proven that drinking is harmful to your health. With the development of medicine, the core metabolic mechanism of drunkenness-related behaviors such as behavioral disorders after drinking has gradually become clear.
For the general public, abstaining from alcohol and limiting alcohol is the most important thing.
Written | Oranhgy Editor | Jessica authorized to reprint, submit and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m).
For more information on the department, please pay attention to Metz's respiratory, neurological, cardiovascular and tumor!
In our country’s wine culture has a long history, almost every festive meal, family and friends gatherings have two drinks.
It is well known that behavioral disorders and other drunken-related behaviors occur after drinking, but the overall situation of the core mechanism of alcohol metabolism is still unclear.
Alcohol, a psychoactive substance that is often abused, causes significant pathology in the entire medical field.
Unlike opioids, nicotine and other psychoactive chemicals, ethanol does not bind to any specific targets or receptors in the brain.
Ethanol metabolites can produce psychoactive effects, which last longer than ethanol in the human body.
Xianjiu liver is the main organ for alcohol detoxification.
Most of the alcohol is first metabolized by the alcohol dehydrogenase (ALDH) in the liver to acetaldehyde, then acetaldehyde dehydrogenase type 2 (ALDH2) is metabolized to acetic acid, and finally eliminated from the body.
Metabolites enter the brain from the liver through the blood and cause movement disorders.
Due to the very low content of various alcohol-metabolizing enzymes in the brain, coupled with the lack of precise and specific research tools, the role of the brain in alcohol metabolism has been ignored.
In addition, people lack understanding of the role of acetic acid (commonly known as acetic acid), a lower metabolite of alcohol.
For a long time, acetic acid has been designated as the non-toxic and harmless metabolic end product of alcohol.
Recently, the team of Professor Zhang Ye from the Department of Anesthesiology and Perioperative Medicine of the Second Affiliated Hospital of Anhui Medical University and Professor Zhang Li from the Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health jointly published a study on Nature Metabolism, which revealed Alcohol causes brain function and behavioral disorders.
ALDH2 catalyzes the production of acetate from alcohol in the brain, which is the main reason for alcohol-induced neurotransmitter changes and behavioral effects in the brain.The research was also selected as the cover paper of the current issue.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z In this study, the researchers first used quantitative PCR to detect the expression of ALDH2 mRNA in different brain regions (Figure 1a) .
Among the 5 tested areas, the expression level of ALDH2 mRNA was the most abundant in the cerebellum and the least in the prefrontal cortex (PFC).
In the detection of ALDH2 enzymatic activity, three different cerebellar subregions showed the highest level of ALDH2 enzymatic activity, which was also the least in PFC.
Subsequently, the researchers used RNAscope technology to perform RNA in situ hybridization.
At low magnification, strong ALDH2 signals were detected in all lobes of the mouse cerebellar sagittal slice (Figure 1b).
The expression of ALDH2 in astrocytes in the cerebellum.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z.
Due to the lack of methods to distinguish between central and peripheral ALDH2 mediated effects, the alcohol metabolism pathway in the brain has an impact on human behavior.
Not yet clear.
To overcome this problem, the researchers constructed ALDH2 knockout mouse models of liver (Aldh2Hep−/−) or astrocytes (Aldh2Gfap−/−).
The results showed that in Aldh2Gfap−/− mice, acetic acid And GABA (an important inhibitory neurotransmitter) did not increase, which also indicates that both acetate and GABA are derived from the ALDH2 enzyme activity in astrocytes.Schematic diagram of the metabolic pathway of ethanol to acetic acid in the liver and brain.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
DOI: 10.
1038 / s42255-021-00357-z GABA levels, and through the GABAergic mechanism to mediate alcohol-induced dyskinesia, which proves that there is a connection between ALDH2 in astrocytes and GABA synthesis and its signaling pathways.
It was also observed that in 3 human and 11 mouse brain samples, ALDH2 can be expressed in cerebellar astrocytes.
As we all know, the cerebellum is the brain area that controls balance and motor coordination.
When ALDH2 is removed from the cerebellar astrocytes, the mice are resistant to dyskinesia caused by drinking alcohol.
Generally, drinking alcohol increases the content of acetate and GABA in the brain; however, when ALDH2 is removed from astrocytes, this increase can be prevented.
In contrast, removing ALDH2 from the liver will not affect the levels of acetate or GABA in the brain.
These findings indicate that the ability of acetic acid produced in the brain and liver to affect motor function is different.
The results of the entire study overturned previous cognition, indicating that acetic acid is an alcohol metabolite related to dyskinesia.
Astrocytes in the cerebellum metabolize ethanol to acetic acid through ALDH2 enzyme.
Acetic acid metabolites increase GABA levels in the cerebellum, and induce the body's drunken balance and motor coordination disorders through the GABAergic mechanism.
Although previous scientific studies believed that the liver produces ALDH2, this study found for the first time that ALDH2 is also present in astrocytes in the brains of mice and humans.
The first author of the article and Dr.
Jin Shiyun from the Department of Anesthesia and Perioperative Medicine of the Second Affiliated Hospital of Anhui Medical University analyzed that, overall, the ALDH2 enzyme has different roles in the liver and brain.
More than 90% of alcohol is metabolized in the liver after drinking, but the products of liver metabolism have little effect on the inhibitory neurotransmitter GABA in the brain.
The metabolism of alcohol in the brain directly causes the increase of GABA, thereby inhibiting brain function, which also suggests that the astrocyte ALDH2 in the brain is the main mechanism of alcohol directly regulating related behavioral damage to the brain.
At the same time, it is recommended to further study the role of this enzyme in humans.
This study suggests that astrocyte ALDH2 may be a useful target for the treatment of alcoholism.
It can be used to regulate the expression of astrocyte ALDH2 to help relieve alcohol, abstain from alcohol, and prevent and treat alcohol-induced brain damage and degeneration.
At the same time, it opens up a new direction for studying the related mechanisms of drunken behavior, and can also provide references for the pathogenesis and treatment of neurological diseases such as dementia (Alzheimer's syndrome).
In fact, the research results are particularly important for Asians, especially East Asians.
In 2020, a joint research team from several Japanese institutions such as the University of Tokyo and the National Cancer Institute in Japan published a study in Science Advances, which pointed out that ALDH2 gene mutations are related to redness on the back of drinking, and people who blush after drinking are at risk of gastric cancer.
Bigger.
In this cross-ethnic study, researchers sequenced the genomes of 531 gastric cancer patients (319 Asian and 212 non-Asian) and divided them into 6 groups based on the mutation characteristics of the tissue samples, Signature 1, 3, 6, 15, 16, 17.
The analysis found that in the Signature 16 group, 70% of patients carried ALDH2 gene mutations, and more than 90% of the patients were Asians, and the average alcohol consumption of patients in this group was not high.
This also means that patients with ALDH2 gene mutations, even if they only drink a small amount of alcohol, will have a significantly increased risk of gastric cancer.
Signature1,3,6,15,16,17 gene mutation analysis.
Defined lifestyle and germline factors predispose Asian populations to gastric cancer.
DOI: 10.
1126/sciadv.
aav9778helloguma and the distribution of ALDH2 genes in different populations around the world is significantly different.
According to researchers from the National Institute of Alcoholism and Alcoholism in the United States and the Kurihama Alcohol Research Center in Japan, about one-third of East Asians lack ALDH2, and about 40% of Asians have genetic defects in alcohol metabolism.
People who carry an ALDH2*2 gene, the ALDH enzyme activity is only 6% of the normal, while the two genes are all ALDH2*2, the ALDH enzyme activity is almost zero, which is the legendary "pour a cup.
"
The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.
doi: 10.
1371/journal.
pmed.
1000050 Among them, the highest is the Han nationality in Guangdong, which is as high as 31%, which is rare in European and American populations.
ALDH2 * Geographical distribution of 504Lys allele frequency.
The gray scale indicates the allele distribution frequency, and the hollow red triangle indicates the position of the overall sample.
The surrounding black lines indicate the frequency boundaries of the 0.
12 and 0.
24 distributions.
Refined Geographic Distribution of the Oriental ALDH2*504Lys(nee487Lys) Variant.
doi:10.
1111/j.
1469-1809.
2009.
00517.
x In summary, for a long time, a large amount of data has proven that drinking is harmful to your health. With the development of medicine, the core metabolic mechanism of drunkenness-related behaviors such as behavioral disorders after drinking has gradually become clear.
For the general public, abstaining from alcohol and limiting alcohol is the most important thing.
Written | Oranhgy Editor | Jessica authorized to reprint, submit and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m).
For more information on the department, please pay attention to Metz's respiratory, neurological, cardiovascular and tumor!
