Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Plant Collection and Preparation of Plu kaow Extract
2.2. Chemicals and Reagents
2.3. Total Phenolic Content (TPC)
2.4. Antioxidant Assays
2.5. Detection of Metabolites Using LC-MS/MS
2.6. Structural Annotation Using MetFrag Webservice
2.7. Metabolite Annotation Using Sirius (v. 5.6.)
2.8. In Silico Analysis
2.9. Hemolytic Activity of Plu kaow Ethanolic Extracts
2.10. Animals
2.11. Diet for the Animals
2.12. Experimental Design
Group 1: | Untreated healthy control rats (HC) |
Group 2: | Untreated diabetic control rats (DC) |
Group 3: | Healthy rats treated with PK ethanolic extract (500 mg/kg/day in 1 mL water) (HPK) |
Group 4: | Diabetic rats treated with PK ethanolic extract (500 mg/kg/day in 1 mL water) (DPK) |
Group 5: | Diabetic rats treated with glibenclamide (5 mg/kg/day in 1 mL water) (DD) |
2.13. Induction of Diabetes in Rats
2.14. Collection of Blood and Determination of Biochemical Parameters
2.15. Histological Investigation
2.16. Statistical Analysis
2.17. Ethical Issues
3. Results
3.1. Effect of Plu kaow on Hyperglycemia of Diabetic and Normal Rats
3.2. Evaluation of the Effect of Plu kaow Ethanolic Extract on Dyslipidemia
3.3. Effect of Plu kaow Ethanolic Extract on Hepatic, Cardiac, and Renal Function Markers Activity
3.4. Effect of Plu kaow Extract on Body Weights and Food Consumption
3.5. Effect of PK Extract on Organs Relative Weight of Liver, Kidney, Heart, Spleen, and Pancreas
3.6. Histopathological Examination of Various Organs of Experimental Rats
3.7. Hemolytic Activity of Plu kaow Ethanolic Extract
3.8. Antioxidant Activity of Plu kaow Ethanolic Extract
3.9. Molecular Docking
3.9.1. Alpha-Amylase
3.9.2. Alpha-Glucosidase
3.9.3. Sulfonylurea Receptor (SUR)
3.9.4. Glucagon Like Peptide-1 (GLP-1)
3.9.5. Insulin-like Growth Factor 1 Kinase (IGF1R)
3.9.6. Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-γ)
3.9.7. Glycogen Phosphorylase-1 (GP-1)
3.10. LC-MS/MS-Based Phytochemical Profiling of the Plu kaow Ethanolic Extract with Structural Annotation Using MetFrag Web Service and Sirius Tandem with CSI:FingerID and CANOPUS
3.10.1. Simple Phenolics
3.10.2. Flavonoids and Glycoside Analogues
3.10.3. Non-Flavonoid Substances
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Healthy Control | Diabetes | ||||||
---|---|---|---|---|---|---|---|
HC | HPK | p | DC | DD | DPK | p | |
Total Cholesterol (mg/dL) | 89.5 ± 9.1 | 94.7 ± 13.5 | ns | 154.0 ± 6.9 | 82.6 ± 5.6 *** | 89.4 ± 5.9 *** | <0.001 |
Triglyceride (mg/dL) | 81.5 ± 11.7 | 59.1 ± 4.1 | ns | 171.3 ± 10.7 | 41.4 ± 11.0 *** | 52.4 ± 11.0 *** | <0.001 |
HDL (mg/dL) | 38.3 ± 9.5 | 60.0 ± 12.4 | ns | 24.2 ± 2.7 | 45.4 ± 2.7 *** | 43.9 ± 2.5 *** | <0.001 |
LDL (mg/dL) | 39.4 ± 3.3 | 29.7 ± 4.8 | ns | 103.1 ± 10.3 | 29.9 ± 5.4 *** | 35.2 ± 5.2 *** | <0.001 |
VLDL (mg/dL) | 12.9 ± 2.2 | 9.2 ± 1.9 | ns | 32.6 ± 2.7 | 8.4 ± 2.4 *** | 10.3 ± 2.2 *** | <0.001 |
TC/HDL ratio | 3.1 ± 0.5 | 1.6 ± 0.14 | <0.05 | 7.4 ± 1.3 | 2.0 ± 0.3 *** | 2.3 ± 0.3 *** | <0.001 |
LDL/HDL ratio | 1.7 ± 0.4 | 0.62 ± 0.15 | ns | 4.6 ± 0.6 | 0.74 ± 0.18 *** | 0.90 ± 0.18 *** | <0.001 |
Healthy Control | Diabetes | ||||||
---|---|---|---|---|---|---|---|
HC | HPK | p | DC | DD | DPK | p | |
SGPT (U/L) | 78.2 ± 9.4 | 93.5 ± 12.3 | ns | 106.4 ± 19.2 | 47.7 ± 8.8 ** | 77.8 ± 12.9 * | * |
SGOT (U/L) | 115.1 ± 17.1 | 86.8 ± 23.8 | ns | 144.3 ± 27.8 | 29.8 ± 7.1 *** | 69.6 ± 18.6 * | * |
AST/ALT Ratio | 1.74 ± 0.27 | 1.39 ± 0.45 | ns | 1.5 ± 0.29 | 0.85 ± 0.23 | 1.0 ± 0.23 | ns |
ALP (U/L) | 193.6 ± 16.4 | 283.9 ± 24.9 | ns | 480.9 ± 117.0 | 255.6 ± 44.9 | 340.9 ± 36.4 | ns |
Sample | Total Phenolic Content | ABTS | DPPH |
---|---|---|---|
(GAE)/g | IC50 (mg/mL) | ||
Plu kaow ethanolic extract | 84.87 | 0.44 | 0.16 |
Gallic acid | - | 0.03 | 0.003 |
Quercetin | - | 0.04 | 0.018 |
Compound | PubChem (CID) | Binding Score/RMSD (Å) | ||||||
---|---|---|---|---|---|---|---|---|
α-Amylase/1.5606 Å * | α-Glucosidase/1.8760 Å ** | SUR/0.8158 Å * | GLP-1/1.3217 Å * | GP/0.7958 Å * | IGF1R/0.2632 Å *** | PPAR-γ/0.6223 Å * | ||
Cinnamic acid | 44539 | 35.49 | 19.50 | 27.33 | 33.28 | 35.31 | 35.17 | 35.14 |
Kaempferol 7-neohesperidoside | 5483905 | 67.74 | 42.87 | 46.65 | 54.59 | 66.83 | 67.50 | 54.63 |
Luteolin | 5280455 | 60.65 | 38.05 | 41.15 | 54.25 | 52.27 | 47.14 | 54.12 |
Epicatechin | 72276 | 55.31 | 35.60 | 36.37 | 55.20 | 52.43 | 51.66 | 57.95 |
Quercetin | 5280343 | 62.41 | 39.36 | 37.98 | 55.22 | 54.64 | 51.49 | 53.62 |
Quercitrin | 5280459 | 58.79 | 42.89 | 45.05 | 62.91 | 65.78 | 54.08 | 62.83 |
Salidroside | 159278 | 54.12 | 37.22 | 38.32 | 53.71 | 54.73 | 55.50 | 51.81 |
Vanillic acid | 8468 | 39.42 | 21.48 | 31.64 | 32.01 | 38.06 | 37.20 | 38.77 |
Neochlorogenic acid | 5280633 | 53.04 | 40.97 | 40.38 | 53.99 | 59.52 | 53.71 | 63.04 |
Vitexin | 5280441 | 54.15 | 45.04 | 44.75 | 50.85 | 60.50 | 51.67 | 70.74 |
Quinic acid | 6508 | 44.20 | 25.17 | 24.86 | 30.32 | 39.60 | 41.99 | 40.01 |
Isochlorogenic acid C | 5315832 | 69.77 | 38.06 | 38.36 | 54.92 | 55.98 | 57.23 | 60.76 |
Guaijaverin | 5481224 | 55.19 | 44.91 | 45.23 | 62.65 | 73.78 | 62.01 | 65.34 |
Rutin | 5280805 | 70.95 | 50.75 | 48.85 | 61.30 | 59.71 | 66.67 | 77.94 |
Afzelin | 5316673 | 59.14 | 41.19 | 44.18 | 61.91 | 63.93 | 53.45 | 62.40 |
Hyperin | 133568467 | 62.06 | 45.35 | 50.10 | 58.82 | 77.11 | 60.11 | 55.13 |
Datiscin | 10054207 | 71.30 | 44.79 | 53.97 | 54.77 | 68.60 | 61.36 | 73.93 |
Shikimic acid | 8742 | 39.01 | 24.59 | 25.84 | 31.69 | 34.82 | 39.21 | 38.12 |
Diosmin | 5281613 | 75.28 | 50.43 | 50.99 | 55.08 | 84.12 | 67.66 | 67.96 |
Apigenin | 5280443 | 55.86 | 37.62 | 35.90 | 53.47 | 51.83 | 44.83 | 51.25 |
Eupatilin | 5273755 | 61.45 | 38.53 | 37.26 | 49.05 | 55.86 | 43.68 | 63.09 |
Rosiglitazone | 77999 | - | - | - | - | - | - | 72.76 |
Acarbose | 9811704 | 66.44 | 49.78 | - | - | - | - | - |
Luteolin † | 5280455 | 37.37 | - | - | - | - | ||
Glibencamide (Glyburide) | 3488 | - | - | 50.76 | - | - | 61.03 | - |
Metformin | 4091 | - | 37.25 | - | - | - | ||
Nojirimycin tetrazole (NTZ) | 41684 | - | - | - | - | 45.32 | - | - |
Glicazide | 3475 | - | - | - | - | 45.93 | - |
No. | UPLC-ESI (-)-QTOF-MS/MS | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Retention Time (min) | Metabolite | Predicted Neutral Formula (Sirius Score %) * | Neutral mass *** | Theoretical (m/z) [M-H]− † | Exp. Mass (m/z) | Mass Error (ppm) ‡ | Library Score (%) # | Rank/DB (F1 Score) | Rank/DB Training (YES/NO) § | |
1 | 0.76 | Quinic acid | C7H12O6 (99%) | 192.06 | 191.0556 | 191.0593 | 19.58 | 89.8 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
2 | 0.65 | Shikimic acid | C7H10O5 (100%) | 174.05 | 173.0450 | 173.0450 | 0 | 100 | 4th/NORMAN (0.7462) | 1st/All Databases (YES) |
3 | 1.88 | Neochlorogenic acid | C16H18O9 (100%) | 354.10 | 353.0873 | 353.0955 | 23.34 | 97.7 | 1st/NORMAN (1.0) | ND. (NO) |
4 | 3.06 | Vanillic acid | C8H8O4 (99.63%) | 168.04 | 167.0344 | 167.0362 | 10.57 | 91.7 | 6th/KEGG (0.7846) | 1st/All Databases (YES) |
5 | 3.78 | Salidroside | C14H20O7 (97.17%) | 300.12 | 299.1131 | 299.1150 | 6.42 | 98.8 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
6 | 4.18 | Epicatechin | C15H14O6 (100%) | 290.08 | 289.0712 | 289.0851 | 48.03 | 90.6 | 1st/NORMAN (1.0) | 1st/All Databases (YES) |
7 | 4.85 | Isochlorogenic acid C | C25H24O12 (90.93%) | 516.13 | 515.1190 | 515.1216 | 5.13 | 86.5 | 7th/PubChem (0.9858) | 1st/All Databases (YES) |
8 | 4.90 | Diosmin | C28H32O15 (N.D) ** | 608.17 | 607.1663 | 607.1352 | −51.22 | 63.3 | 1st/KEGG (1.0) | ND. (NO) |
9 | 5.01 | Rutin | C27H30O16 (100%) | 610.15 | 609.1455 | 609.1544 | 14.61 | 96.0 | 2nd/NORMAN (0.0) | 1st/All Databases (YES) |
10 | 5.07 | Vitexin | C21H20O10 (100%) | 432.11 | 431.0987 | 431.1025 | 10.84 | 96.3 | 3th/NORMAN (1.0) | 1st/All Databases (YES) |
11 | 5.85 | Afzelin | C21H20O10 (94.77%) | 432.11 | 431.0987 | 431.10015 | 5.39 | 95.2 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
12 | 5.18 | Hyperin | C21H20O12 (100%) | 464.10 | 463.0877 | 463.0958 | 17.59 | 99.5 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
13 | 5.29 | Datiscin | C27H30O15 (79.27%) | 594.16 | 593.1507 | 593.1549 | 7.17 | 99.4 | ND. | 5th/All Databases (YES) |
14 | 5.40 | Guaijaverin | C20H18O11 (100%) | 434.08 | 433.0771 | 433.0804 | 7.64 | 95.6 | 1st/NORMAN (1.0) | 1st/All Databases (YES) |
15 | 5.57 | Quercitrin | C21H20O11 (100%) | 448.10 | 447.0927 | 447.1004 | 17.13 | 99.5 | 1st/NORMAN (1.0) | 1st/All Databases (YES) |
16 | 6.35 | Kaempferol-7-O-neohesperidroside | C27H30O15 (N.D.) ** | 594.16 | 593.1507 | 593.1339 | −28.24 | 100 | 1st/NORMAN (1.0) | ND. (NO) |
17 | 6.41 | Cinnamic acid | C9H8O2 (99.95%) | 148.05 | 147.0446 | 147.0460 | 9.49 | 95.3 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
18 | 6.52 | Luteolin | C15H10O6 (95.80%) | 286.05 | 285.0399 | 285.0419 | 6.96 | 94.8 | 1st/KEGG (1.0) | 1st/All Databases (YES) |
19 | 6.58 | Quercetin | C15H10O7 (92.71%) | 302.04 | 301.0348 | 301.0373 | 8.21 | 97.5 | 1st/NORMAN (1.0) | 1st/All Databases (YES) |
20 | 7.08 | Apigenin | C15H10O5 (98.89%) | 270.05 | 269.0450 | 269.0475 | 9.29 | 99.3 | 1st/KEGGs (1.0) | 1st/All Databases (YES) |
21 | 8.42 | Eupatilin | C18H16O7 (100%) | 344.09 | 343.0818 | 343.0839 | 6.18 | 98.9 | 3rd/KEGG (0.988) | 3rd/All Databases 2nd/KEGG 1st/HMDB |
Mechanism of Action | Target Compounds of PK Containing Anti-Diabetic Properties | References |
---|---|---|
Inhibition of α-amylase activity | Kaempferol 7-neohesperidoside, isochlorogenic acid, rutin, datiscin, diosmin | [59,60,61,62,63,64] |
Inhibition of α-glucosidase activity | Datiscin, diosmin, rutin, isochlorogenic acid | [59,60,61,62,63,64] |
Regulation of sulfonylurea receptor (SUR) | Diosmin, datiscin, hyperin | [63,65,66] |
Inhibition of Glycogen phosphorylase | Kaempferol, glycosidic flavonoids, rutin, hyperin, datiscin, guaijaverin, afzelin, and diosmin | [67,68,69,70] |
Release of glucagon-like peptide-1 (GLP-1) | Guaijaverin, afzelin, rutin, quercitrin, salidroside, isochlorogenic acid C, neochlorogenic acid | [71,72,73,74] |
Modulation of insulin-like growth factor 1 (IGF1R) kinase | Kaempferol 7-neohesperidoside, guaijaverin, rutin, datiscin, diosmin | [75,76,77] |
Inhibition of Peroxisome proliferator-activated receptor-gamma (PPAR-γ) | Rutin, kaempferol, datiscin, diosmin | [78,79,80] |
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Rahman, S.S.; Klamrak, A.; Nopkuesuk, N.; Nabnueangsap, J.; Janpan, P.; Choowongkomon, K.; Daduang, J.; Daduang, S. Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies. Antioxidants 2024, 13, 1064. https://doi.org/10.3390/antiox13091064
Rahman SS, Klamrak A, Nopkuesuk N, Nabnueangsap J, Janpan P, Choowongkomon K, Daduang J, Daduang S. Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies. Antioxidants. 2024; 13(9):1064. https://doi.org/10.3390/antiox13091064
Chicago/Turabian StyleRahman, Shaikh Shahinur, Anuwatchakij Klamrak, Napapuch Nopkuesuk, Jaran Nabnueangsap, Piyapon Janpan, Kiattawee Choowongkomon, Jureerut Daduang, and Sakda Daduang. 2024. "Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies" Antioxidants 13, no. 9: 1064. https://doi.org/10.3390/antiox13091064