Multitargeted Effects of Plantago ovata Ethanol Extract in Experimental Rat Streptozotocin-Induced Diabetes Mellitus and Letrozole-Induced Polycystic Ovary Syndrome
Abstract
1. Introduction
2. Results
2.1. Plant Extract Phytochemical Characterization
2.2. Assessment of the In Vitro OS Markers
2.3. Evaluation of In Vivo Antioxidant Effects of P. ovata Ethanol Extract
2.4. In Vivo Inflammatory Markers Analysis
2.5. Assessment of In Vivo Metabolic and Hepatoprotective Activities
2.6. Effect of P. ovata Ethanolic Extract on Sex Hormones, Serum Insulin, and HOMA-IR in Rat LET-Induced PCOS
2.7. Principal Component Analysis of Serum Biomarkers
2.8. Histological and Follicular Changes in Letrozole-Induced Hyperandrogenized Rat Ovaries Following Treatment with P. ovata Ethanolic Extract
2.9. Ultrasonography Findings
3. Discussion
4. Materials and Methods
4.1. Chemicals
4.2. Extraction and Preparation of P. ovata Ethanol Extract
4.3. Quantification of Total Phenolic and Flavonoid Content
4.4. Chromatographic and Mass Spectrometric Profiling
4.5. Evaluation of In Vitro Antioxidant Activity
4.6. Experimental Design
- CONTROL: non-diabetic, untreated.
- STZ: diabetic control group (STZ 55 mg/kg, i.p.) [92].
- STZ + TX: diabetic rats treated with TX (20 mg/kg b.w.) [34].
- STZ + M: diabetic rats treated with metformin (100 mg/100 g b.w.) [91].
- POEE100%, POEE50%, and POEE25%: diabetic rats receiving 100%, 50%, and 25% dilutions of POEE, respectively.
- CONTROL: untreated, healthy control.
- LET: PCOS group receiving LET (1 mg/kg b.w., orally) [93].
- LET + TX: PCOS rats treated with TX (20 mg/kg b.w., orally).
- LET + M: PCOS rats treated with metformin (100 mg/100 g b.w., orally).
- LET + POEE100%: PCOS rats treated with 100% POEE dilution.
4.7. Pharmacological Studies
4.7.1. Evaluation of the Serum OS Markers
4.7.2. Assessment of Serum Inflammatory Biomarkers
4.7.3. Evaluation of the Blood Glucose, Lipid Profile, Triglyceride–Glucose Index, Liver Injury, and Anthropometric Parameters
4.7.4. Hormonal Assays
4.8. Histopathological Assessment of Reproductive Organs
4.9. Ultrasonographic Evaluation
4.10. Statistical Methods
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
DM | Diabetes Mellitus |
PCOS | Polycystic ovary syndrome |
POEE | Plantago ovata ethanol extract |
STZ | Streptozotocin |
LET | Letrozole |
OS | Oxidative stress |
ROS | Reactive oxygen species |
TX | Trolox |
TPC | Total phenolic content |
TFC | Total flavonoid content |
TOS | Total oxidative status |
TAC | Total antioxidant capacity |
OSI | Oxidative stress index |
MDA | Malondialdehyde |
AOPPs | Advanced oxidation protein products |
8-OHdG | 8-Hydroxydeoxyguanosine |
NO | Nitric oxide |
3-NT | 3-Nitrotyrosine |
AGEs | Advanced glycation end products |
SH | Total thiols |
NF-kB-p65 | Nuclear Factor Kappa B-p65 |
IL-1B | Interleukin-1 Beta |
IL-18 | Interleukin-18. |
IL-10 | Interleukin-10 |
GLU | Blood glucose |
LH | Luteinizing hormone |
FSH | Follicle-stimulating hormone |
TyG | Triglyceride–Glucose index |
IR | Insulin resistance |
HOMA-IR | Homeostatic Model Assessment for Insulin Resistance |
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Peak No. | Rt (min) | UV λmax (nm) | [M + H]+ (m/z) | Compound | Subclass | Quantity * (μg/mL) |
---|---|---|---|---|---|---|
1 | 12.85 | 350,255 | 595,287 | Kaempferol-rutinoside | Flavonol | 98.695 ± 6.23 |
2 | 14.51 | 355,250 | 743,303 | Quercetin-xylosyl-rutinoside | Flavonol | 419.322 ± 25.98 |
3 | 15.04 | 355,250 | 611,303 | Quercetin-rutinoside (Rutin) | Flavonol | 259.952 ± 8.34 |
4 | 15.39 | 355,250 | 465,303 | Quercetin-glucoside | Flavonol | 225.034 ± 17.11 |
5 | 16.12 | 345,250 | 611,287 | Luteolin-diglucoside | Flavone | 36.901 ± 0.78 |
6 | 16.97 | 355,250 | 479,303 | Quercetin-glucuronide | Flavonol | 73.309 ± 4.65 |
7 | 17.76 | 350,255 | 611,287 | Kaempferol-diglucoside | Flavonol | 86.271 ± 7.43 |
Sample | DPPH (μgTE/mL) | H2O2 Scavenging Activity (μgTE/mL) | NO Scavenging Activity (μgQE/mL) | FRAP (mgTE/mL) |
---|---|---|---|---|
P. ovata IC50 | 99.86 ± 4.32 | 87.06 ± 2.89 | 121.07 ± 16.22 | 92.58 ± 5.14 |
TX IC50 | 11.2 ± 1.7 | 24.23 ± 3.12 | - | 12.07 ± 2.04 |
Quercetin IC50 | - | - | 20.58 ± 3.67 | - |
p-value | <0.001 | <0.001 | <0.001 | <0.001 |
Parameters | Control | STZ | STZ + POEE100% | STZ + POEE50% | STZ + POEE25% | STZ + M | STZ + TX |
---|---|---|---|---|---|---|---|
TOS (μM/L) | 18.11 ± 3.18 | 40.85 ± 3.18 aaa | 15.35 ± 3.18 bbb,ccc | 21.43 ± 3.18 bbb | 36.98 ± 3.18 b | 23.17 ± 3.18 bbb | 25.18 ± 11.55 bbb |
TAC (mM/L) | 1.09 ± 0.001 | 1.084 ± 0.0014 a | 1.089 ± 0.001 bbb,c | 1.088 ± 0.001 bbb,c | 1.09 ± 0.0001 bbb | 1.091 ± 0.001 bb | 1.09 ± 0.001 b |
OSI | 120.96 ± 2.53 | 37.67 ± 2.92 aaa | 14.08 ± 2.92 bbb | 19.47 ± 2.92 bbb,cc | 33.25 ± 2.92 b | 21.24 ± 2.92 bbb | 24.30 ± 12.54 b |
MDA (nM/L) | 2.33 ± 0.04 | 3.53 ± 0.04 aaa | 2.31 ± 0.04 bbb | 2.58 ± 0.04 bbb | 2.86 ± 0.04 bbb | 2.13 ± 0.04 bbb | 2.20 ± 0.18 bbb |
AOPP (μM/L) | 140.40 ± 7.77 | 166.66 ± 7.77 aaa | 118.93 ± 7.77 bbb,cc,dd | 121.67 ± 7.77 bbb,cc,dd | 139.11 ± 7.77 b,c,d | 161.59 ± 26.19 | 166.08 ± 36.79 |
8-OHdG (ng/mL) | 38.04 ± 12.36 | 45.45 ± 12.36 a | 23.68 ± 12.36 bb,c | 17.80 ± 12.36 bb,cc,dd | 30.20 ± 12.36 b | 44.63 ± 12.36 | 41.71 ± 31.66 |
AGEs (ng/mL) | 11.18 ± 2.88 | 14.71 ± 2.88 a | 12.42 ± 2.88 b | 14.07 ± 2.88 cc | 13.42 ± 2.88 c | 11.01 ± 2.88 bb | 14.76 ± 2.12 |
NOx (μM/L) | 31.38 ± 5.33 | 60.58 ± 5.33 aaa | 44.48 ± 5.33 bb,cc | 42.44 ± 5.33 bb,cc | 49.49 ± 5.33 | 57.83 ± 5.33 | 58.19 ± 5.45 |
3NT (ng/mL) | 36.86 ± 12.28 | 58.82 ± 12.28 a | 21.00 ± 12.28 bbb,cc,ddd | 19.27 ± 12.28 bbb,cc,ddd | 27.80 ± 12.28 bbb,cc,dd | 44.54 ± 12.28 b | 64.71 ± 46.28 |
SH (μM/L) | 322.84 ± 14.47 | 253.13 ± 14.47 a | 387.77 ± 14.47 bb,cc,d | 414.63 ± 14.47 bb | 254.83 ± 14.47 cc,dd | 507.52 ± 150.89 bbb | 426.53 ± 109.40 bb |
Parameters | Control | LET | LET + POEE100% | LET + M | LET + TX |
---|---|---|---|---|---|
TOS (μM/L) | 4.80 ± 0.46 | 14.40 ± 0.88 aaa | 12.29 ± 2.93 b,ddd | 13.15 ± 4.41 | 4.55 ± 0.36 bbb |
TAC (mM/L) | 1.09 ± 0.0001 | 1.079 ± 0.0001 aaa | 1.083 ± 0.0001 bbb | 1.09 ± 0.0001 bbb | 1.08 ± 0.0001 bbb |
OSI | 4.44 ± 0.34 | 12.45 ± 1.42 aaa | 11.18 ± 1.12 b,ddd | 12.43 ± 3.74 | 4.24 ± 0.28 bbb |
MDA (nM/L) | 2.12 ± 0.31 | 3.84 ± 0.20 aaa | 2.78 ± 0.35 bb | 2.96 ± 0.27 bbb | 2.46 ± 0.44 bbb |
AOPP (μM/L) | 57.54 ± 4.32 | 97.64 ± 8.05 aaa | 80.64 ± 8.20 bb | 77.88 ± 12.16 bb | 84.10 ± 12.25 b |
8-OHdG (ng/mL) | 109.05 ± 2.30 | 148.34 ± 48.09 aa | 48.97 ± 14.61 bbb,c | 75.53 ± 24.30 bb | 37.67 ± 8.75 bbb |
AGEs (ng/mL) | 20.54 ± 10.79 | 30.69 ± 7.69 a | 18.81 ± 6.09 | 18.39 ± 1.12 | 15.64 ± 6.20 |
NOx (μM/L) | 35.38 ± 5.48 | 63.89 ± 2.55 aaa | 60.00 ± 11.90 bb,c | 64.68 ± 7.33 | 64.73 ± 10.23 |
3NT (ng/mL) | 28.24 ± 7.12 | 59.07 ± 32.99 aa | 59.60 ± 31.33 | 65.70 ± 37.60 | 51.46 ± 34.43 |
SH (μM/L) | 363.83 ± 27.24 | 304.70 ± 31.11 aaa | 319.04 ± 6.70 | 351.83 ± 41.71 b | 355.20 ± 62.51 b |
Parameters | Control | STZ | STZ + POEE100% | STZ + POEE50% | STZ + POEE25% | STZ + M | STZ + TX |
---|---|---|---|---|---|---|---|
NFkB-p65 (pg/mL) | 165.37 ± 32.29 | 314.29 ± 59.94 aaa | 196.73 ± 55.44 bb,c,d | 231.17 ± 42.75 b | 256.67 ± 43.79 b | 230.48 ± 18.46 b | 223.32 ± 34.26 b |
IL-1B (pg/mL) | 24.38 ± 3.92 | 132.33 ± 20.18 aaa | 19.62 ± 2.66 bbb,ddd | 20.85 ± 5.54 bbb,d | 26.49 ± 18.77 bbb | 19.61 ± 3.93 bbb | 27.91 ± 3.15 bbb |
IL-18 (pg/mL) | 17.28 ± 8.12 | 60.12 ± 10.88 aaa | 0.01 ± 0.0002 bbb,ccc,ddd | 0.012 ± 0.0001 bbb,ccc,ddd | 0.0109 ± 0.0003 bbb,ccc,ddd | 11.50 ± 1.28 bbb | 12.182 ± 0.55 bbb |
Gasdermin (ng/mL) | 6.002 ± 1.05 | 9.84 ± 1.27 aa | 5.25 ± 0.43 bb,cc | 5.77 ± 0.97 bb,cc | 6.13 ± 1.04 | 9.29 ± 1.05 | 6.51 ± 1.35 |
Parameters | Control | LET | LET + POEE100% | LET + M | LET + TX |
---|---|---|---|---|---|
NFkB-p65 (pg/mL) | 258.35 ± 48.76 | 520.89 ± 73.55 aa | 281.30 ± 71.59 bb,cc | 541.52 ± 93.95 | 268.39 ± 90.45 bb |
IL-1B (pg/mL) | 24.99 ± 1.60 | 44.06 ± 10.21 aa | 24.43 ± 3.66 bb | 22.17 ± 3.35 bb | 27.15 ± 0.89 bb |
IL-18 (pg/mL) | 19.47 ± 2.48 | 33.20 ± 7.30 aa | 17.76 ± 3.67 bb | 16.03 ± 1.08 bbb | 20.92 ± 6.16 b |
IL-10 (ng/mL) | 15.79 ± 2.19 | 29.66 ± 5.81 aaa | 16.01 ± 2.25 bbb,dd | 14.44 ± 2.77 bbb | 23.00 ± 1.46 b |
Parameters | Control | STZ | STZ + POEE100% | STZ + POEE50% | STZ + POEE25% | STZ + M | STZ + TX |
---|---|---|---|---|---|---|---|
GLU (mg/dL) | 102.91 ± 8.39 | 426.76 ± 26.71 aaa | 360.51 ± 38.69 bb | 411.98 ± 36.79 | 422.25 ± 56.36 | 370.72 ± 49.08 bb | 412.5 ± 139.36 |
TG (mg/dL) | 66.10 ± 23.86 | 129.26 ± 6.15 aaa | 92.96 ± 19.59 b,ccc,dd | 102.99 ± 12.25 b,cc,d | 113.00 ± 12.41 c,d | 133.09 ± 5.33 | 116.62 ± 7.53 b |
TyG index | 4.38 ± 0.12 | 5.46 ± 0.11 aa | 5.20 ± 0.11 b | 5.32 ± 0.65 bb | 5.38 ± 0.13 | 5.40 ± 0.06 | 5.38 ± 0.11 |
TC (mg/dL) | 72.97 ± 12.33 | 123.51 ± 8.21 aaa | 72.95 ± 12.09 bbb,ccc | 98.03 ± 12.12 bbb | 105.83 ± 6.99 bbb,c | 98.06 ± 12.27 bbb,dd | 112.36 ± 12.75 |
AST (U/L) | 67.51 ± 15.04 | 156.8 ± 16.04 aaa | 119.06 ± 34.73 bb | 114.78 ± 20.13 bb | 125.61 ± 25.35 | 125.42 ± 24.38 | 131.07 ± 28.54 |
ALT (U/L) | 62.87 ± 14.38 | 159.92 ± 18.24 aaa | 104.18 ± 32.003 bb | 117.48 ± 22.41 bb | 130.55 ± 24.53 | 126.76 ± 16.03 b | 137.79 ± 42.05 |
AST/ALT | 1.08 ± 0.10 | 0.98 ± 0.03 aa | 1.04 ± 0.09 | 0.98 ± 0.18 | 0.96 ± 0.09 | 0.98 ± 0.18 | 0.94 ± 0.102 |
BW (g) change | 15.14 ± 3.30 | 104.16 ± 26.62 aaa | 33.54 ± 13.46 bb | 64.63 ± 20.03 b,cc | 67.39 ± 22.46 b,cc | 27.39 ± 15.01 bb | 56.25 ± 18.55 bb |
Parameters | Control | LET | LET + POEE100% | LET + M | LET + TX |
---|---|---|---|---|---|
Insulin (pg/mL) | 30.15 ± 6.63 | 99.53 ± 12.59 aaa | 24.08 ± 4.30 bbb | 25.81 ± 4.85 bbb | 27.89 ± 8.44 bbb |
HOMA-IR | 7.91 ± 3.34 | 32.59 ± 8.86 aaa | 5.74 ± 4.38 bbb | 7.11 ± 4.43 bbb | 7.14 ± 2.41 bbb |
GLU (mg/dL) | 100.97 ± 19.57 | 129.45 ± 12.59 a | 77.69 ± 14.20 bbb,c,d | 104.49 ± 5.94 b | 108.92 ± 18.02 b |
FSH (mIU/ml) | 39.19 ± 4.48 | 99.86 ± 33.16 aa | 80.39 ± 18.30 c | 99.33 ± 3.70 | 101.13 ± 34.50 |
LH (mIU/ml) | 9.97 ± 4.66 | 26.05 ± 10.10 aa | 14.60 ± 5.87 b,c | 20.69 ± 14.05 | 13.12 ± 2.97 b |
Estrogen (pg/mL) | 596.34 ± 67.74 | 329.88 ± 55.80 aaa | 728.07 ± 166.13 bbb | 774.90 ± 55.74 bbb | 621.89 ± 166.06 bbb |
Testosterone (ng/mL) | 0.76 ± 0.24 | 1.17 ± 0.83 a | 1.31 ± 0.17 b | 1.55 ± 1.05 | 2.44 ± 0.75 |
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Usatiuc, L.-O.; Pop, R.M.; Adrian, S.; Pârvu, M.; Țicolea, M.; Uifălean, A.; Vălean, D.; Gavrilaș, L.-I.; Csilla-Enikő, S.; Leopold, L.F.; et al. Multitargeted Effects of Plantago ovata Ethanol Extract in Experimental Rat Streptozotocin-Induced Diabetes Mellitus and Letrozole-Induced Polycystic Ovary Syndrome. Int. J. Mol. Sci. 2025, 26, 4712. https://doi.org/10.3390/ijms26104712
Usatiuc L-O, Pop RM, Adrian S, Pârvu M, Țicolea M, Uifălean A, Vălean D, Gavrilaș L-I, Csilla-Enikő S, Leopold LF, et al. Multitargeted Effects of Plantago ovata Ethanol Extract in Experimental Rat Streptozotocin-Induced Diabetes Mellitus and Letrozole-Induced Polycystic Ovary Syndrome. International Journal of Molecular Sciences. 2025; 26(10):4712. https://doi.org/10.3390/ijms26104712
Chicago/Turabian StyleUsatiuc, Lia-Oxana, Raluca Maria Pop, Surd Adrian, Marcel Pârvu, Mădălina Țicolea, Ana Uifălean, Dan Vălean, Laura-Ioana Gavrilaș, Szabo Csilla-Enikő, Loredana Florina Leopold, and et al. 2025. "Multitargeted Effects of Plantago ovata Ethanol Extract in Experimental Rat Streptozotocin-Induced Diabetes Mellitus and Letrozole-Induced Polycystic Ovary Syndrome" International Journal of Molecular Sciences 26, no. 10: 4712. https://doi.org/10.3390/ijms26104712
APA StyleUsatiuc, L.-O., Pop, R. M., Adrian, S., Pârvu, M., Țicolea, M., Uifălean, A., Vălean, D., Gavrilaș, L.-I., Csilla-Enikő, S., Leopold, L. F., Ranga, F., Cătoi, F. A., & Pârvu, A. E. (2025). Multitargeted Effects of Plantago ovata Ethanol Extract in Experimental Rat Streptozotocin-Induced Diabetes Mellitus and Letrozole-Induced Polycystic Ovary Syndrome. International Journal of Molecular Sciences, 26(10), 4712. https://doi.org/10.3390/ijms26104712