Qi‐dan‐dihuang decoction ameliorates renal fibrosis in diabetic rats via p38MAPK/AKT/mTOR signaling pathway
Context Qi‐dan‐dihuang decoction (QDD) has been used to treat diabetic kidney disease (DKD), but the underlying mechanisms are poorly understood. Objective This study reveals the mechanism by which QDD ameliorates DKD. Materials and Methods The compounds in QDD were identified by high‐performance li...
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| Veröffentlicht in: | Environmental toxicology 2024-06, Vol.39 (6), p.3481-3499 |
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| creator | Kuang, Liuyan You, Yanting Qi, Jieying Chen, Jieyu Zhou, Xinghong Ji, Shuai Cheng, Jingru Kwan, Hiu Yee Jiang, Pingping Sun, Xiaomin Su, Mengting Wang, Ming Chen, Wenxiao Luo, Ren Zhao, Xiaoshan Zhou, Lin |
| description | Context
Qi‐dan‐dihuang decoction (QDD) has been used to treat diabetic kidney disease (DKD), but the underlying mechanisms are poorly understood.
Objective
This study reveals the mechanism by which QDD ameliorates DKD.
Materials and Methods
The compounds in QDD were identified by high‐performance liquid chromatography and quadrupole‐time‐of‐flight tandem mass spectrometry (HPLC‐Q‐TOF‐MS). Key targets and signaling pathways were screened through bioinformatics. Nondiabetic Lepr db/m mice were used as control group, while Lepr db/db mice were divided into model group, dapagliflozin group, 1% QDD‐low (QDD‐L), and 2% QDD‐high (QDD‐H) group. After 12 weeks of administration, 24 h urinary protein, serum creatinine, and blood urea nitrogen levels were detected. Kidney tissues damage and fibrosis were evaluated by pathological staining. In addition, 30 mmol/L glucose‐treated HK‐2 and NRK‐52E cells to induce DKD model. Cell activity and migration capacity as well as protein expression levels were evaluated.
Results
A total of 46 key target genes were identified. Functional enrichment analyses showed that key target genes were significantly enriched in the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) and mitogen‐activated protein kinase (MAPK) signaling pathways. In addition, in vivo and in vitro experiments confirmed that QDD ameliorated renal fibrosis in diabetic mice by resolving inflammation and inhibiting the epithelial‐mesenchymal transition (EMT) via the p38MAPK and AKT‐mammalian target of rapamycin (mTOR) pathways.
Discussion and Conclusion
QDD inhibits EMT and the inflammatory response through the p38MAPK and AKT/mTOR signaling pathways, thereby playing a protective role in renal fibrosis in DKD. |
| doi_str_mv | 10.1002/tox.24179 |
| format | Article |
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Qi‐dan‐dihuang decoction (QDD) has been used to treat diabetic kidney disease (DKD), but the underlying mechanisms are poorly understood.
Objective
This study reveals the mechanism by which QDD ameliorates DKD.
Materials and Methods
The compounds in QDD were identified by high‐performance liquid chromatography and quadrupole‐time‐of‐flight tandem mass spectrometry (HPLC‐Q‐TOF‐MS). Key targets and signaling pathways were screened through bioinformatics. Nondiabetic Lepr db/m mice were used as control group, while Lepr db/db mice were divided into model group, dapagliflozin group, 1% QDD‐low (QDD‐L), and 2% QDD‐high (QDD‐H) group. After 12 weeks of administration, 24 h urinary protein, serum creatinine, and blood urea nitrogen levels were detected. Kidney tissues damage and fibrosis were evaluated by pathological staining. In addition, 30 mmol/L glucose‐treated HK‐2 and NRK‐52E cells to induce DKD model. Cell activity and migration capacity as well as protein expression levels were evaluated.
Results
A total of 46 key target genes were identified. Functional enrichment analyses showed that key target genes were significantly enriched in the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) and mitogen‐activated protein kinase (MAPK) signaling pathways. In addition, in vivo and in vitro experiments confirmed that QDD ameliorated renal fibrosis in diabetic mice by resolving inflammation and inhibiting the epithelial‐mesenchymal transition (EMT) via the p38MAPK and AKT‐mammalian target of rapamycin (mTOR) pathways.
Discussion and Conclusion
QDD inhibits EMT and the inflammatory response through the p38MAPK and AKT/mTOR signaling pathways, thereby playing a protective role in renal fibrosis in DKD.</description><identifier>ISSN: 1520-4081</identifier><identifier>ISSN: 1522-7278</identifier><identifier>EISSN: 1522-7278</identifier><identifier>DOI: 10.1002/tox.24179</identifier><identifier>PMID: 38456329</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Animals ; Bioinformatics ; Cell Line ; Cell migration ; Chromatography ; Creatinine ; Damage detection ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - drug therapy ; diabetic kidney disease ; Diabetic Nephropathies - drug therapy ; Diabetic Nephropathies - pathology ; Drugs, Chinese Herbal - pharmacology ; epithelial‐mesenchymal transition ; Fibrosis ; Genes ; High performance liquid chromatography ; HPLC ; Humans ; Inflammation ; Inflammatory response ; Kidney - drug effects ; Kidney - pathology ; Kidney diseases ; Kidneys ; Kinases ; Liquid chromatography ; Male ; MAP kinase ; Mass spectrometry ; Mass spectroscopy ; Mice ; network pharmacology ; p38 Mitogen-Activated Protein Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Qi‐dan‐dihuang decoction ; Quadrupoles ; Rapamycin ; Rats ; Rats, Sprague-Dawley ; renal fibrosis ; Signal transduction ; Signal Transduction - drug effects ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Urea</subject><ispartof>Environmental toxicology, 2024-06, Vol.39 (6), p.3481-3499</ispartof><rights>2024 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-817d98ec2de97101b0da4847188dd030fea290fb3fdef0d0c5692aa154c852a13</citedby><cites>FETCH-LOGICAL-c3539-817d98ec2de97101b0da4847188dd030fea290fb3fdef0d0c5692aa154c852a13</cites><orcidid>0000-0003-2952-6543</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Ftox.24179$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Ftox.24179$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38456329$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuang, Liuyan</creatorcontrib><creatorcontrib>You, Yanting</creatorcontrib><creatorcontrib>Qi, Jieying</creatorcontrib><creatorcontrib>Chen, Jieyu</creatorcontrib><creatorcontrib>Zhou, Xinghong</creatorcontrib><creatorcontrib>Ji, Shuai</creatorcontrib><creatorcontrib>Cheng, Jingru</creatorcontrib><creatorcontrib>Kwan, Hiu Yee</creatorcontrib><creatorcontrib>Jiang, Pingping</creatorcontrib><creatorcontrib>Sun, Xiaomin</creatorcontrib><creatorcontrib>Su, Mengting</creatorcontrib><creatorcontrib>Wang, Ming</creatorcontrib><creatorcontrib>Chen, Wenxiao</creatorcontrib><creatorcontrib>Luo, Ren</creatorcontrib><creatorcontrib>Zhao, Xiaoshan</creatorcontrib><creatorcontrib>Zhou, Lin</creatorcontrib><title>Qi‐dan‐dihuang decoction ameliorates renal fibrosis in diabetic rats via p38MAPK/AKT/mTOR signaling pathway</title><title>Environmental toxicology</title><addtitle>Environ Toxicol</addtitle><description>Context
Qi‐dan‐dihuang decoction (QDD) has been used to treat diabetic kidney disease (DKD), but the underlying mechanisms are poorly understood.
Objective
This study reveals the mechanism by which QDD ameliorates DKD.
Materials and Methods
The compounds in QDD were identified by high‐performance liquid chromatography and quadrupole‐time‐of‐flight tandem mass spectrometry (HPLC‐Q‐TOF‐MS). Key targets and signaling pathways were screened through bioinformatics. Nondiabetic Lepr db/m mice were used as control group, while Lepr db/db mice were divided into model group, dapagliflozin group, 1% QDD‐low (QDD‐L), and 2% QDD‐high (QDD‐H) group. After 12 weeks of administration, 24 h urinary protein, serum creatinine, and blood urea nitrogen levels were detected. Kidney tissues damage and fibrosis were evaluated by pathological staining. In addition, 30 mmol/L glucose‐treated HK‐2 and NRK‐52E cells to induce DKD model. Cell activity and migration capacity as well as protein expression levels were evaluated.
Results
A total of 46 key target genes were identified. Functional enrichment analyses showed that key target genes were significantly enriched in the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) and mitogen‐activated protein kinase (MAPK) signaling pathways. In addition, in vivo and in vitro experiments confirmed that QDD ameliorated renal fibrosis in diabetic mice by resolving inflammation and inhibiting the epithelial‐mesenchymal transition (EMT) via the p38MAPK and AKT‐mammalian target of rapamycin (mTOR) pathways.
Discussion and Conclusion
QDD inhibits EMT and the inflammatory response through the p38MAPK and AKT/mTOR signaling pathways, thereby playing a protective role in renal fibrosis in DKD.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Bioinformatics</subject><subject>Cell Line</subject><subject>Cell migration</subject><subject>Chromatography</subject><subject>Creatinine</subject><subject>Damage detection</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>diabetic kidney disease</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>epithelial‐mesenchymal transition</subject><subject>Fibrosis</subject><subject>Genes</subject><subject>High performance liquid chromatography</subject><subject>HPLC</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>Kidney - drug effects</subject><subject>Kidney - pathology</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Kinases</subject><subject>Liquid chromatography</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Mice</subject><subject>network pharmacology</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Qi‐dan‐dihuang decoction</subject><subject>Quadrupoles</subject><subject>Rapamycin</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>renal fibrosis</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Urea</subject><issn>1520-4081</issn><issn>1522-7278</issn><issn>1522-7278</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc9u1DAQhy0EoqVw4AWQJS7lkO74X2wfVxUF1FYLaJG4WY7ttK6SeImTtnvjEXhGngS323JA4uLx4ZtPM_ND6DWBIwJAF1O6PaKcSP0E7RNBaSWpVE_v_1BxUGQPvcj5CgB0LernaI8pLmpG9T5KX-Lvn7-8He7eeDnb4QL74JKbYhqw7UMX02inkPEYBtvhNjZjyjHjOGAfbROm6HABMr6OFm-YOl9-Pl0sT9eLfr36inO8KF2xSDd2uryx25foWWu7HF491AP07eT9-vhjdbb68Ol4eVY5JpiuFJFeq-CoD1oSIA14yxWXRCnvgUEbLNXQNqz1oQUPTtSaWksEd0pQS9gBOtx5N2P6MYc8mT5mF7rODiHN2VAtuJS1ELygb_9Br9I8lrGzYSC4IpQyWah3O8qV_fMYWrMZY2_HrSFg7lIwJQVzn0Jh3zwY56YP_i_5ePYCLHbATezC9v8ms1593yn_AJW4kp4</recordid><startdate>202406</startdate><enddate>202406</enddate><creator>Kuang, Liuyan</creator><creator>You, Yanting</creator><creator>Qi, Jieying</creator><creator>Chen, Jieyu</creator><creator>Zhou, Xinghong</creator><creator>Ji, Shuai</creator><creator>Cheng, Jingru</creator><creator>Kwan, Hiu Yee</creator><creator>Jiang, Pingping</creator><creator>Sun, Xiaomin</creator><creator>Su, Mengting</creator><creator>Wang, Ming</creator><creator>Chen, Wenxiao</creator><creator>Luo, Ren</creator><creator>Zhao, Xiaoshan</creator><creator>Zhou, Lin</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</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>7QH</scope><scope>7ST</scope><scope>7TN</scope><scope>7U7</scope><scope>7UA</scope><scope>C1K</scope><scope>F1W</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M7N</scope><scope>SOI</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2952-6543</orcidid></search><sort><creationdate>202406</creationdate><title>Qi‐dan‐dihuang decoction ameliorates renal fibrosis in diabetic rats via p38MAPK/AKT/mTOR signaling pathway</title><author>Kuang, Liuyan ; You, Yanting ; Qi, Jieying ; Chen, Jieyu ; Zhou, Xinghong ; Ji, Shuai ; Cheng, Jingru ; Kwan, Hiu Yee ; Jiang, Pingping ; Sun, Xiaomin ; Su, Mengting ; Wang, Ming ; Chen, Wenxiao ; Luo, Ren ; Zhao, Xiaoshan ; Zhou, Lin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-817d98ec2de97101b0da4847188dd030fea290fb3fdef0d0c5692aa154c852a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Bioinformatics</topic><topic>Cell Line</topic><topic>Cell migration</topic><topic>Chromatography</topic><topic>Creatinine</topic><topic>Damage detection</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>diabetic kidney disease</topic><topic>Diabetic Nephropathies - drug therapy</topic><topic>Diabetic Nephropathies - pathology</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>epithelial‐mesenchymal transition</topic><topic>Fibrosis</topic><topic>Genes</topic><topic>High performance liquid chromatography</topic><topic>HPLC</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Inflammatory response</topic><topic>Kidney - drug effects</topic><topic>Kidney - pathology</topic><topic>Kidney diseases</topic><topic>Kidneys</topic><topic>Kinases</topic><topic>Liquid chromatography</topic><topic>Male</topic><topic>MAP kinase</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Mice</topic><topic>network pharmacology</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Qi‐dan‐dihuang decoction</topic><topic>Quadrupoles</topic><topic>Rapamycin</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>renal fibrosis</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Urea</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuang, Liuyan</creatorcontrib><creatorcontrib>You, Yanting</creatorcontrib><creatorcontrib>Qi, Jieying</creatorcontrib><creatorcontrib>Chen, Jieyu</creatorcontrib><creatorcontrib>Zhou, Xinghong</creatorcontrib><creatorcontrib>Ji, Shuai</creatorcontrib><creatorcontrib>Cheng, Jingru</creatorcontrib><creatorcontrib>Kwan, Hiu Yee</creatorcontrib><creatorcontrib>Jiang, Pingping</creatorcontrib><creatorcontrib>Sun, Xiaomin</creatorcontrib><creatorcontrib>Su, Mengting</creatorcontrib><creatorcontrib>Wang, Ming</creatorcontrib><creatorcontrib>Chen, Wenxiao</creatorcontrib><creatorcontrib>Luo, Ren</creatorcontrib><creatorcontrib>Zhao, Xiaoshan</creatorcontrib><creatorcontrib>Zhou, Lin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aqualine</collection><collection>Environment Abstracts</collection><collection>Oceanic Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Water Resources Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Environmental toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuang, Liuyan</au><au>You, Yanting</au><au>Qi, Jieying</au><au>Chen, Jieyu</au><au>Zhou, Xinghong</au><au>Ji, Shuai</au><au>Cheng, Jingru</au><au>Kwan, Hiu Yee</au><au>Jiang, Pingping</au><au>Sun, Xiaomin</au><au>Su, Mengting</au><au>Wang, Ming</au><au>Chen, Wenxiao</au><au>Luo, Ren</au><au>Zhao, Xiaoshan</au><au>Zhou, Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Qi‐dan‐dihuang decoction ameliorates renal fibrosis in diabetic rats via p38MAPK/AKT/mTOR signaling pathway</atitle><jtitle>Environmental toxicology</jtitle><addtitle>Environ Toxicol</addtitle><date>2024-06</date><risdate>2024</risdate><volume>39</volume><issue>6</issue><spage>3481</spage><epage>3499</epage><pages>3481-3499</pages><issn>1520-4081</issn><issn>1522-7278</issn><eissn>1522-7278</eissn><abstract>Context
Qi‐dan‐dihuang decoction (QDD) has been used to treat diabetic kidney disease (DKD), but the underlying mechanisms are poorly understood.
Objective
This study reveals the mechanism by which QDD ameliorates DKD.
Materials and Methods
The compounds in QDD were identified by high‐performance liquid chromatography and quadrupole‐time‐of‐flight tandem mass spectrometry (HPLC‐Q‐TOF‐MS). Key targets and signaling pathways were screened through bioinformatics. Nondiabetic Lepr db/m mice were used as control group, while Lepr db/db mice were divided into model group, dapagliflozin group, 1% QDD‐low (QDD‐L), and 2% QDD‐high (QDD‐H) group. After 12 weeks of administration, 24 h urinary protein, serum creatinine, and blood urea nitrogen levels were detected. Kidney tissues damage and fibrosis were evaluated by pathological staining. In addition, 30 mmol/L glucose‐treated HK‐2 and NRK‐52E cells to induce DKD model. Cell activity and migration capacity as well as protein expression levels were evaluated.
Results
A total of 46 key target genes were identified. Functional enrichment analyses showed that key target genes were significantly enriched in the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) and mitogen‐activated protein kinase (MAPK) signaling pathways. In addition, in vivo and in vitro experiments confirmed that QDD ameliorated renal fibrosis in diabetic mice by resolving inflammation and inhibiting the epithelial‐mesenchymal transition (EMT) via the p38MAPK and AKT‐mammalian target of rapamycin (mTOR) pathways.
Discussion and Conclusion
QDD inhibits EMT and the inflammatory response through the p38MAPK and AKT/mTOR signaling pathways, thereby playing a protective role in renal fibrosis in DKD.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>38456329</pmid><doi>10.1002/tox.24179</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0003-2952-6543</orcidid></addata></record> |
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| ispartof | Environmental toxicology, 2024-06, Vol.39 (6), p.3481-3499 |
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| source | Wiley-Blackwell Journals; MEDLINE |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Animals Bioinformatics Cell Line Cell migration Chromatography Creatinine Damage detection Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - drug therapy diabetic kidney disease Diabetic Nephropathies - drug therapy Diabetic Nephropathies - pathology Drugs, Chinese Herbal - pharmacology epithelial‐mesenchymal transition Fibrosis Genes High performance liquid chromatography HPLC Humans Inflammation Inflammatory response Kidney - drug effects Kidney - pathology Kidney diseases Kidneys Kinases Liquid chromatography Male MAP kinase Mass spectrometry Mass spectroscopy Mice network pharmacology p38 Mitogen-Activated Protein Kinases - metabolism Proteins Proto-Oncogene Proteins c-akt - metabolism Qi‐dan‐dihuang decoction Quadrupoles Rapamycin Rats Rats, Sprague-Dawley renal fibrosis Signal transduction Signal Transduction - drug effects TOR protein TOR Serine-Threonine Kinases - metabolism Urea |
| title | Qi‐dan‐dihuang decoction ameliorates renal fibrosis in diabetic rats via p38MAPK/AKT/mTOR signaling pathway |
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