Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway
Objective To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE −/− mice. Methods Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE −/− mice were fed a high-fat diet for 12 weeks, according to a completely random me...
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| description | Objective
To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE
−/−
mice.
Methods
Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE
−/−
mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe
2+
in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively.
Results
BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (
P |
| doi_str_mv | 10.1007/s11655-024-3666-z |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3095677465</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3095677465</sourcerecordid><originalsourceid>FETCH-LOGICAL-c226t-8fca975fdbb4985e0aa63301a926f6ef6eb9ecf53b254dc65c41c17c191cc9ea3</originalsourceid><addsrcrecordid>eNp9kE1LAzEQhoMofv8AL5Kjl7X52GSbYy1WhaLFKngL2XS2G9nu1iSL2F9vStWjMMwMzDsvMw9CF5RcU0KKQaBUCpERlmdcSplt9tAxVYpnJCdsP_WyYKmn4gidhPBOiCgkEYfoiKvtaMiPUXUDvgTvWsAPbe1KFwOegPfdOnbBBWzaBZ5HU7rGbSDgUazBd8E2KUdn8awxHz3gWPuuX9b48XnCBvPpuBhROribveV4ZmL9ab7O0EFlmgDnP_UUvU5uX8b32fTp7mE8mmaWMRmzYWWNKkS1KMtcDQUQYyTnhBrFZCUhRanAVoKXTOQLK4XNqaWFpYpaq8DwU3S18137Lh0Wol65YKFpTAtdHzQnSsiiyKVIUrqT2vRQ8FDptXcr4780JXqLV-_w6oRXb_HqTdq5_LHvyxUs_jZ-eSYB2wlCGrVL8Pq9632bXv7H9RvMlYaA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3095677465</pqid></control><display><type>article</type><title>Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway</title><source>MEDLINE</source><source>SpringerLink</source><source>Alma/SFX Local Collection</source><creator>Wang, Ting-ting ; Yu, Li-li ; Zheng, Jun-meng ; Han, Xin-yi ; Jin, Bo-yuan ; Hua, Cheng-jun ; Chen, Yu-shan ; Shang, Sha-sha ; Liang, Ya-zhou ; Wang, Jian-ru</creator><creatorcontrib>Wang, Ting-ting ; Yu, Li-li ; Zheng, Jun-meng ; Han, Xin-yi ; Jin, Bo-yuan ; Hua, Cheng-jun ; Chen, Yu-shan ; Shang, Sha-sha ; Liang, Ya-zhou ; Wang, Jian-ru</creatorcontrib><description><![CDATA[Objective
To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE
−/−
mice.
Methods
Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE
−/−
mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe
2+
in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively.
Results
BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (
P
<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe
2+
in BBR group was significantly lower than that in the model group (
P
<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (
P
<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (
P
<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (
P
<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe
2+
, MDA and ROS levels increased (
P
<0.05 or
P
<0.01), and the activity of SOD decreased (
P
<0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (
P
<0.01).
Conclusion
Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects.]]></description><identifier>ISSN: 1672-0415</identifier><identifier>ISSN: 1993-0402</identifier><identifier>EISSN: 1993-0402</identifier><identifier>DOI: 10.1007/s11655-024-3666-z</identifier><identifier>PMID: 39167283</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Amino Acid Transport System y ; Animals ; Berberine - pharmacology ; Ferroptosis - drug effects ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2 - metabolism ; Original Article ; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism ; Plaque, Atherosclerotic - drug therapy ; Plaque, Atherosclerotic - pathology ; Signal Transduction - drug effects</subject><ispartof>Chinese journal of integrative medicine, 2024-10, Vol.30 (10), p.906-916</ispartof><rights>The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature 2024</rights><rights>2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c226t-8fca975fdbb4985e0aa63301a926f6ef6eb9ecf53b254dc65c41c17c191cc9ea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11655-024-3666-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11655-024-3666-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27933,27934,41497,42566,51328</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39167283$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Ting-ting</creatorcontrib><creatorcontrib>Yu, Li-li</creatorcontrib><creatorcontrib>Zheng, Jun-meng</creatorcontrib><creatorcontrib>Han, Xin-yi</creatorcontrib><creatorcontrib>Jin, Bo-yuan</creatorcontrib><creatorcontrib>Hua, Cheng-jun</creatorcontrib><creatorcontrib>Chen, Yu-shan</creatorcontrib><creatorcontrib>Shang, Sha-sha</creatorcontrib><creatorcontrib>Liang, Ya-zhou</creatorcontrib><creatorcontrib>Wang, Jian-ru</creatorcontrib><title>Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway</title><title>Chinese journal of integrative medicine</title><addtitle>Chin. J. Integr. Med</addtitle><addtitle>Chin J Integr Med</addtitle><description><![CDATA[Objective
To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE
−/−
mice.
Methods
Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE
−/−
mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe
2+
in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively.
Results
BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (
P
<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe
2+
in BBR group was significantly lower than that in the model group (
P
<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (
P
<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (
P
<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (
P
<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe
2+
, MDA and ROS levels increased (
P
<0.05 or
P
<0.01), and the activity of SOD decreased (
P
<0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (
P
<0.01).
Conclusion
Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects.]]></description><subject>Amino Acid Transport System y</subject><subject>Animals</subject><subject>Berberine - pharmacology</subject><subject>Ferroptosis - drug effects</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Original Article</subject><subject>Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism</subject><subject>Plaque, Atherosclerotic - drug therapy</subject><subject>Plaque, Atherosclerotic - pathology</subject><subject>Signal Transduction - drug effects</subject><issn>1672-0415</issn><issn>1993-0402</issn><issn>1993-0402</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LAzEQhoMofv8AL5Kjl7X52GSbYy1WhaLFKngL2XS2G9nu1iSL2F9vStWjMMwMzDsvMw9CF5RcU0KKQaBUCpERlmdcSplt9tAxVYpnJCdsP_WyYKmn4gidhPBOiCgkEYfoiKvtaMiPUXUDvgTvWsAPbe1KFwOegPfdOnbBBWzaBZ5HU7rGbSDgUazBd8E2KUdn8awxHz3gWPuuX9b48XnCBvPpuBhROribveV4ZmL9ab7O0EFlmgDnP_UUvU5uX8b32fTp7mE8mmaWMRmzYWWNKkS1KMtcDQUQYyTnhBrFZCUhRanAVoKXTOQLK4XNqaWFpYpaq8DwU3S18137Lh0Wol65YKFpTAtdHzQnSsiiyKVIUrqT2vRQ8FDptXcr4780JXqLV-_w6oRXb_HqTdq5_LHvyxUs_jZ-eSYB2wlCGrVL8Pq9632bXv7H9RvMlYaA</recordid><startdate>20241001</startdate><enddate>20241001</enddate><creator>Wang, Ting-ting</creator><creator>Yu, Li-li</creator><creator>Zheng, Jun-meng</creator><creator>Han, Xin-yi</creator><creator>Jin, Bo-yuan</creator><creator>Hua, Cheng-jun</creator><creator>Chen, Yu-shan</creator><creator>Shang, Sha-sha</creator><creator>Liang, Ya-zhou</creator><creator>Wang, Jian-ru</creator><general>Springer Nature Singapore</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20241001</creationdate><title>Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway</title><author>Wang, Ting-ting ; Yu, Li-li ; Zheng, Jun-meng ; Han, Xin-yi ; Jin, Bo-yuan ; Hua, Cheng-jun ; Chen, Yu-shan ; Shang, Sha-sha ; Liang, Ya-zhou ; Wang, Jian-ru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c226t-8fca975fdbb4985e0aa63301a926f6ef6eb9ecf53b254dc65c41c17c191cc9ea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Amino Acid Transport System y</topic><topic>Animals</topic><topic>Berberine - pharmacology</topic><topic>Ferroptosis - drug effects</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Original Article</topic><topic>Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism</topic><topic>Plaque, Atherosclerotic - drug therapy</topic><topic>Plaque, Atherosclerotic - pathology</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Ting-ting</creatorcontrib><creatorcontrib>Yu, Li-li</creatorcontrib><creatorcontrib>Zheng, Jun-meng</creatorcontrib><creatorcontrib>Han, Xin-yi</creatorcontrib><creatorcontrib>Jin, Bo-yuan</creatorcontrib><creatorcontrib>Hua, Cheng-jun</creatorcontrib><creatorcontrib>Chen, Yu-shan</creatorcontrib><creatorcontrib>Shang, Sha-sha</creatorcontrib><creatorcontrib>Liang, Ya-zhou</creatorcontrib><creatorcontrib>Wang, Jian-ru</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chinese journal of integrative medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Ting-ting</au><au>Yu, Li-li</au><au>Zheng, Jun-meng</au><au>Han, Xin-yi</au><au>Jin, Bo-yuan</au><au>Hua, Cheng-jun</au><au>Chen, Yu-shan</au><au>Shang, Sha-sha</au><au>Liang, Ya-zhou</au><au>Wang, Jian-ru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway</atitle><jtitle>Chinese journal of integrative medicine</jtitle><stitle>Chin. J. Integr. Med</stitle><addtitle>Chin J Integr Med</addtitle><date>2024-10-01</date><risdate>2024</risdate><volume>30</volume><issue>10</issue><spage>906</spage><epage>916</epage><pages>906-916</pages><issn>1672-0415</issn><issn>1993-0402</issn><eissn>1993-0402</eissn><abstract><![CDATA[Objective
To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE
−/−
mice.
Methods
Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE
−/−
mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe
2+
in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively.
Results
BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (
P
<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe
2+
in BBR group was significantly lower than that in the model group (
P
<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (
P
<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (
P
<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (
P
<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe
2+
, MDA and ROS levels increased (
P
<0.05 or
P
<0.01), and the activity of SOD decreased (
P
<0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (
P
<0.01).
Conclusion
Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects.]]></abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>39167283</pmid><doi>10.1007/s11655-024-3666-z</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1672-0415 |
| ispartof | Chinese journal of integrative medicine, 2024-10, Vol.30 (10), p.906-916 |
| issn | 1672-0415 1993-0402 1993-0402 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3095677465 |
| source | MEDLINE; SpringerLink; Alma/SFX Local Collection |
| subjects | Amino Acid Transport System y Animals Berberine - pharmacology Ferroptosis - drug effects Male Medicine Medicine & Public Health Mice Mice, Inbred C57BL NF-E2-Related Factor 2 - metabolism Original Article Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism Plaque, Atherosclerotic - drug therapy Plaque, Atherosclerotic - pathology Signal Transduction - drug effects |
| title | Berberine Inhibits Ferroptosis and Stabilizes Atherosclerotic Plaque through NRF2/SLC7A11/GPX4 Pathway |
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