Drug Information

Drug (ID: DG00165) and It's Reported Resistant Information

• Name: Metformin
• Synonyms: 657-24-9; 1,1-Dimethylbiguanide; N,N-dimethylimidodicarbonimidic diamide; Metiguanide; Dimethylbiguanide; Glucophage; Haurymelin; Gliguanid; Fluamine; Glumetza; Flumamine; Melbin; Diabex; N,N-Dimethylbiguanide; Metformina; Metforminum; Metformine; Islotin; Glifage; Siofor; N1,N1-Dimethylbiguanide; DMGG; NNDG; Dimethyldiguanide; N,N-Dimethyldiguanide; Metformina [DCIT]; Imidodicarbonimidic diamide, N,N-dimethyl-; Metformina [Spanish]; Metforminum [INN-Latin]; Metformine [INN-French]; Metformin [USAN:INN:BAN]; 1,1-Dimethyl; Diabetosan; Dimethylbiguanidine; Dimethylguanylguanidine; Glycon; Diabex (TN); Diaformin (TN); Dianben (TN); Fortamet (TN); Gen-Metformin; Glucophage (TN); Glumetza (TN); LA-6023; Nu-Metformin; Obimet (TN); Riomet (TN); Metformin (USAN/INN); 1,1-Dimethyl biguanide; 3-(diaminomethylidene)-1,1-dimethylguanidine; [14C]metformin
• Indication:
  In total 1 Indication(s)
  Type 2 diabetes mellitus [ICD-11: 5A11]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Pancreatic cancer [ICD-11: 2C10]; [2]
• Target: Acetyl-CoA carboxylase 2 (ACACB); ACACB_HUMAN; [1]
• Target: Solute carrier family 47 member 1 (SLC47A1); S47A1_HUMAN; [1]
• Formula: C4H11N5
• IsoSMILES: CN(C)C(=N)N=C(N)N
• InChI: 1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
• InChIKey: XZWYZXLIPXDOLR-UHFFFAOYSA-N
• PubChem CID: 4091
• ChEBI ID: CHEBI:6801
• TTD Drug ID: D0D7LA
• VARIDT ID: DR00133
• DrugBank ID: DB00331

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Cervical cancer [ICD-11: 2C77]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [1]

• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Cervical cancer [ICD-11: 2C77]
• The Specified Disease: Cervical & endocervical cancer
• The Studied Tissue: Cervix Uteri
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.06E-02; Fold-change: -2.59E+00; Z-score: -3.07E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Wound-healing assay; Transwell assay
• Mechanism Description: Metformin inhibits the expression of MALAT1 and upregulates miR-142-3p in cervical cancer cells.

Key Molecule: hsa-miR-142-3p [1]

• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Molecule Alteration: Demethylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Wound-healing assay; Transwell assay
• Mechanism Description: Metformin inhibits the expression of MALAT1 and upregulates miR-142-3p in cervical cancer cells.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Integrin beta-1 (ITGB1) [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 A cells; Blood; Homo sapiens (Human); CVCL_0374
• Experiment for Molecule Alteration: qPCR; qRT-PCR
• Experiment for Drug Resistance: Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
• Mechanism Description: We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Key Molecule: Platelet endothelial cell adhesion molecule (PECAM1) [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 A cells; Blood; Homo sapiens (Human); CVCL_0374
• Experiment for Molecule Alteration: qPCR; qRT-PCR
• Experiment for Drug Resistance: Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
• Mechanism Description: We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Key Molecule: Endoglin (ENG) [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 A cells; Blood; Homo sapiens (Human); CVCL_0374
• Experiment for Molecule Alteration: qPCR; qRT-PCR
• Experiment for Drug Resistance: Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
• Mechanism Description: We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Key Molecule: CD9 antigen (CD9) [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KG-1 A cells; Blood; Homo sapiens (Human); CVCL_0374
• Experiment for Molecule Alteration: qPCR; qRT-PCR
• Experiment for Drug Resistance: Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
• Mechanism Description: We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 1 (CDK1) [4]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: Cyclin-A2 (CCNA2) [4]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: G2/mitotic-specific cyclin-B1 (CCNB1) [4]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate carboxylase (PC) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT1A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression.

Key Molecule: Pyruvate carboxylase (PC) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT2A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression.

Key Molecule: Pyruvate carboxylase (PC) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT3A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression.

Skin squamous cell carcinoma [ICD-11: 2C31]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: AMP-activated protein kinase (AMPK) [5]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Squamous cell carcinoma [ICD-11: 2C31.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: PDT resistant cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: SCC13 cells; Skin; Homo sapiens (Human); CVCL_4029
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.

Key Molecule: AMP-activated protein kinase (AMPK) [5]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Squamous cell carcinoma [ICD-11: 2C31.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• In Vivo Model: Nude mice, 10GT SCC13 cells; nude mice, PDT. P cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.

ICD-05: Endocrine/nutritional/metabolic diseases

Type 2 diabetes mellitus [ICD-11: 5A11]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Solute carrier family 2 member 4 (SLC2A4) [6]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

Key Molecule: Peroxisome proliferator-activated receptor gamma (PPARG) [6]

• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

ICD-09: Visual system diseases

Retinopathy [ICD-11: 9B71]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Parkinson disease protein 7 homolog (PARK7) [7]

• Sensitive Disease: Diabetic retinopathy [ICD-11: 9B71.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL staining assay
• Mechanism Description: After DJ-1 overexpression, apoptosis of rat retinal pericytes (RRPs) decreased, the ratio of B-cell lymphoma-2 (Bcl-2) to BCL2-Associated X Protein (BAX) increased, the production of ROS decreased, and the protein expression and activity of manganese superoxide dismutase (MnSOD, also called SOD2) and catalase (CAT) increased. DJ-1 overexpression activated Nrf2 expression, however, after Nrf2 silencing, apoptosis of RRPs increased, the ratio of Bcl-2 to BAX decreased, the production of ROS increased, the protein expression of MnSOD and CAT decreased, and the expression of heme oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) decreased.

References

• Ref 1: Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells. Eur J Pharmacol. 2018 Jul 5;830:59-67. doi: 10.1016/j.ejphar.2018.04.027. Epub 2018 Apr 25.
• Ref 2: Inhibition of pyruvate carboxylase reverses metformin resistance by activating AMPK in pancreatic cancer. Life Sci. 2023 Aug 15;327:121817.
• Ref 3: Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. Genes (Basel). 2024 May 20;15(5):648.
• Ref 4: Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells. Leuk Res Treatment. 2015;2015:516460. doi: 10.1155/2015/516460. Epub 2015 Nov 25.
• Ref 5: Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy. Mol Metab. 2022 Jun;60:101496.
• Ref 6: Chebulagic acid attenuates HFD/streptozotocin induced impaired glucose metabolism and insulin resistance via up regulations of PPAR Gamma and GLUT 4 in type 2 diabetic rats. Toxicol Mech Methods. 2022 Mar;32(3):159-170. doi: 10.1080/15376516.2021.1976333. Epub 2021 Sep 22.
• Ref 7: DJ-1 protects retinal pericytes against high glucose-induced oxidative stress through the Nrf2 signaling pathway. Sci Rep. 2020 Feb 12;10(1):2477. doi: 10.1038/s41598-020-59408-2.