Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals Breeding and Ethical Approval
2.2. Procedures
2.2.1. Selection of Dose(s) and Route of Administration
2.2.2. Acute Toxicity
2.2.3. Sub-Acute Toxicity
2.2.4. Pre-Clinical Observations and Survival
2.2.5. Biochemical Assessment
2.2.6. Histological Evaluation
2.3. Statistical Analysis
3. Results
3.1. Acute Toxicity
3.2. Sub-Acute Toxicity
3.2.1. Body Weights
3.2.2. Biochemical Assessment
Liver
Kidney
Pancreas
Heart
3.2.3. Histopathological Evaluation
Effect on Liver
Effect on Kidney
Effect on Pancreas
Effect on Heart
4. Discussion
5. Conclusions
6. Study Limitations and Future Plan
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Groups | Days of Treatment | Biochemical Tests | n | Mean | Skewness | z-Value | Kurtosis | z-Value | ||
---|---|---|---|---|---|---|---|---|---|---|
Statistic | Statistic | Statistic | Std. Error | Statistic | Std. Error | |||||
Control | 11th day | Blood Urea Nitrogen (mg/dL) | 6 | 13.33 | 0.248 | 0.845 | 0.293 | −0.014 | 1.741 | −0.008 |
Serum creatinine (mg/dL) | 6 | 0.517 | −0.313 | 0.845 | −0.370 | −0.104 | 1.741 | −0.059 | ||
Alanine aminotransferase (ALT) U/L | 6 | 94.50 | −0.574 | 0.845 | −0.679 | −1.132 | 1.741 | −0.650 | ||
Aspartate aminotransferase (AST) U/L | 6 | 24.00 | 0.433 | 0.845 | 0.512 | −1.175 | 1.741 | −0.674 | ||
Valid N (listwise) | 6 | |||||||||
21st day | Blood Urea Nitrogen (mg/dL) | 6 | 15.17 | 0.319 | 0.845 | 0.377 | −1.171 | 1.741 | −0.672 | |
Serum creatinine (mg/dL) | 6 | 0.483 | 0.313 | 0.845 | 0.370 | −0.104 | 1.741 | −0.059 | ||
Alanine aminotransferase (ALT) U/L | 6 | 92.17 | −0.036 | 0.845 | −0.042 | 0.428 | 1.741 | 0.245 | ||
Aspartate aminotransferase (AST) U/L | 6 | 24.67 | −0.224 | 0.845 | −0.265 | −1.864 | 1.741 | −1.070 | ||
Valid N (listwise) | 6 | |||||||||
Treatment | 11th day | Blood Urea Nitrogen (mg/dL) | 6 | 26.67 | 0.435 | 0.845 | 0.514 | 0.586 | 1.741 | 0.336 |
Serum creatinine (mg/dL) | 6 | 0.483 | 0.313 | 0.845 | 0.370 | −0.104 | 1.741 | −0.059 | ||
Alanine aminotransferase (ALT) U/L | 6 | 98.00 | −0.515 | .845 | −0.609 | 0.729 | 1.741 | 0.418 | ||
Aspartate aminotransferase (AST) U/L | 6 | 25.50 | 0.461 | 0.845 | 0.545 | −1.260 | 1.741 | −0.723 | ||
Valid N (listwise) | 6 | |||||||||
21st day | Blood Urea Nitrogen (mg/dL) | 6 | 18.50 | 0.000 | 0.845 | 0 | −1.200 | 1.741 | −0.689 | |
Serum creatinine (mg/dL) | 6 | 0.500 | 0.000 | 0.845 | 0 | −1.875 | 1.741 | −1.076 | ||
Alanine aminotransferase (ALT) U/L | 6 | 94.50 | 0.401 | 0.845 | 0.474 | 1.635 | 1.741 | 0.939 | ||
Aspartate aminotransferase (AST) U/L | 6 | 24.50 | 0.255 | 0.845 | 0.301 | −1.312 | 1.741 | −0.753 | ||
Valid N (listwise) | 6 |
Levene’s Test for Equality of Variances—11th Day | Levene’s Test for Equality of Variances—21st Day | |||
---|---|---|---|---|
F | Sig. | F | Sig. | |
Blood urea Nitrogen (mg/dL) | 0.741 | 0.410 | 1.250 | 0.290 |
Serum creatinine (mg/dL) | 0.000 | 1.000 | 0.160 | 0.698 |
Alanine aminotransferase (ALT) U/L | 0.877 | 0.371 | 2.094 | 0.178 |
Aspartate aminotransferase (AST) U/L | 0.030 | 0.865 | 1.042 | 0.331 |
Group | Statistical Parameter | Alanine Aminotransferase (ALT, 11th day) | Alanine Aminotransferase (ALT, 21st day) | Aspartate Aminotransferase (AST, 11th day) | Aspartate Aminotransferase (AST, 21st day) |
---|---|---|---|---|---|
Control (n = 6) | Mean ± SD | 94.50 ± 5.089 | 92.17 ± 5.456 | 24.00 ± 3.464 | 24.67 ± 2.805 |
Minimum | 87 | 84 | 20 | 21 | |
Maximum | 100 | 100 | 29 | 28 | |
Treatment (n = 6) | Mean ± SD | 98 ± 3.742 | 94.50 ± 15.681 | 25.50 ± 3.082 | 24.50 ± 3.834 |
Minimum | 92 | 72 | 22 | 20 | |
Maximum | 103 | 120 | 30 | 30 | |
Treated vs. control | p-value | 0.205 | 0.738 | 0.447 | 0.933 |
Treated (11th day) vs. treated (21st day) | p-value | 0.606 | 0.629 |
Group | Statistical Parameter | Blood Urea Nitrogen (BUN, 11th Day) | Blood Urea Nitrogen (BUN, 21st Day) | Serum Creatinine (11th Day) | Serum Creatinine (21st Day) |
---|---|---|---|---|---|
Control | Mean ± SD | 13.33 ± 1.75 | 18.50 ± 1.871 | 0.517 ± 0.075 | 0.500 ± 0.0894 |
Minimum | 11 | 16 | 0.4 | 0.4 | |
Maximum | 16 | 21 | 0.6 | 0.6 | |
Treatment | Mean ± SD | 26.67 ± 2.73 | 15.17 ± 2.639 | 0.483 ± 0.075 | 0.483 ±0.0753 |
Minimum | 23 | 12 | 0.4 | 0.4 | |
Maximum | 31 | 19 | 0.6 | 0.6 | |
Treated vs. control | p-value | 0 | 0.03 | 0.461 | 0.734 |
Treated (11th vs. 21st day) | p-value | 0 | 0.734 |
Group | Statistical Parameter | Serum Amylase (U/L) (11th Day) | Serum Amylase (U/L) (21st Day) | Random Blood Glucose (mg/dL) (11th Day) | Random Blood Glucose (mg/dL) (21st Day) |
---|---|---|---|---|---|
Control (n = 6) | Mean ± SD | 2683.17 ± 26.649 | 2680 ± 23.421 | 83.83 ± 7.35 | 69.33 ± 9.07 |
Minimum | 2649 | 2655 | 73 | 60 | |
Maximum | 2720 | 2700 | 90 | 85 | |
Treatment (n = 6) | Mean ± SD | 2680 ± 23.45 | 2672 ± 17.07 | 43.66 ± 13.89 | 56.67 ± 6.18 |
Minimum | 2655 | 2650 | 23 | 48 | |
Maximum | 2710 | 2700 | 65 | 65 | |
Treated vs. control | p-value | 0.831 | 0.515 | 0.000 | 0.018 |
Treated (11th day) vs. treated (21st day) | p-value | 0.184 | 0.508 |
Group | Statistical Parameter | Random Blood Glucose (mg/dL) | Random Blood Glucose (mg/dL) | Random Blood Glucose (mg/dL) | Random Blood Glucose (mg/dL) |
---|---|---|---|---|---|
Time Period | Baseline | 7th Day | 11th Day | - | |
Control (n = 6) | Mean ± SD | 83.57 ± 7.232 | 82.67 ± 4.179 | 83.83 ± 7.360 | - |
Minimum | 74 | 79 | 73 | - | |
Maximum | 92 | 90 | 91 | - | |
Treatment (n = 6) | Mean ± SD | 82.17 ± 4.535 | 60.33 ± 3.011 | 47.83 ± 9.517 | - |
Minimum | 78 | 572 | 39 | - | |
Maximum | 90 | 66 | 65 | - | |
Treated vs. control | p-value | 0.710 | 0.000 | 0.000 | - |
Time Period | Baseline | 7th Day | 14th Day | 21st Day | |
Control (n = 6) | Mean ± SD | 72.50 ± 4.722 | 75.50 ± 6.979 | 75.83 ± 6.555 | 69.33 ± 9.070 |
Minimum | 70 | 69 | 68 | 60 | |
Maximum | 69 | 85 | 85 | 85 | |
Treatment (n = 6) | Mean ± SD | 80.83 ± 9.042 | 60.00 ± 7.563 | 56.17 ± 4.355 | 56.67 ± 6.186 |
Minimum | 74 | 79 | 73 | 48 | |
Maximum | 92 | 90 | 91 | 65 | |
Treated vs. control | p-value | 0.073 | 0.004 | 0.000 | 0.018 |
Group | Statistical Parameter | Cardiac Troponin-I (ng/dL) (cTn-I, 11th Day) | Cardiac Troponin-I (ng/dL) (cTn-I, 21st Day) | Creatinine Kinase-Myocardial Band (U/L) (CK-MB, 11th Day) | Creatinine Kinase-Myocardial Band (U/L) (CK-MB, 21st Day) |
---|---|---|---|---|---|
Control (n = 6) | Mean ± SD | 0.29667 ± 0.055 | 0.25833 ± 0.02483 | 11 ± 2.098 | 13.83 ± 1.871 |
Minimum | 0.25 | 0.23 | 9 | 8 | |
Maximum | 0.4 | 0.27 | 14 | 12 | |
Treatment (n = 6) | Mean ± SD | 0.3 ± 0.0522 | 0.26167 ± 0.0286 | 13.83 ± 2.14 | 13.67 ± 2.160 |
Minimum | 0.26 | 0.22 | 12 | 11 | |
Maximum | 0.4 | 0.3 | 16 | 17 | |
Treated vs. control | p-value | 0.916 | 0.834 | 0.672 | 0.896 |
Treated (11th day) vs. treated (21st day) | p-value | 0.497 | 0.786 |
Histopathological Findings | Animal Group-I | Animal Group-II | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
(Control) | (Treated) | |||||||||||
1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 | |
Kidney | ||||||||||||
Hyperemia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
Inflammatory cell aggregation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 1 |
Fibrosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
Glomerular injury | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 1 | 2 | 1 |
Steatosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 |
Ectasia/tubular injury | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 2 | 2 |
Liver | ||||||||||||
Hyperemia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Inflammatory cell aggregation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 1 |
Fibrosis | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 |
Steatosis | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 3 | 2 | 2 | 2 |
Scoring of Pancreas Tissue Slides | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
on 11th Day | Control Animals | Treated Animals | ||||||||||
Parameters | 1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 |
Edema | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 1 |
Necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 0 |
Inflammation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 1 | 1 | 1 |
Hemorrhage | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Fat necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
on 21st Day | Control Animals | Treated Animals | ||||||||||
Parameters | 1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 |
Edema | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 3 | 3 | 2 | 4 |
Necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 1 | 1 | 2 |
Inflammation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 2 | 1 | 3 |
Hemorrhage | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Fat necrosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Scoring of Heart Tissue Slides | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
on 11th Day | Control Animals | Treated Animals | ||||||||||
Parameters | 1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 |
Focal myocytes damage | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 3 | 2 | 2 | 2 |
Multifocal degeneration | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 2 | 2 | 2 | 2 |
Multifocal degeneration with inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 0 | 1 | 1 |
Myofibrillar degeneration/diffuse inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Necrosis with diffuse inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
on 21st Day | Control Animals | Treated Animals | ||||||||||
Scoring Parameters | 1 | 2 | 3 | 4 | 5 | 6 | 1 | 2 | 3 | 4 | 5 | 6 |
Focal myocytes damage | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 3 | 3 | 3 | 3 |
Multifocal degeneration | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 3 | 3 | 3 | 3 |
Multifocal degeneration with inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 3 | 3 | 3 | 2 |
Myofibrillar degeneration/diffuse inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 3 | 2 | 2 |
Necrosis with diffuse inflammatory process | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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Kamil, M.; Fatima, A.; Ullah, S.; Ali, G.; Khan, R.; Ismail, N.; Qayum, M.; Irimie, M.; Dinu, C.G.; Ahmedah, H.T.; et al. Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques. Toxics 2021, 9, 119. https://doi.org/10.3390/toxics9060119
Kamil M, Fatima A, Ullah S, Ali G, Khan R, Ismail N, Qayum M, Irimie M, Dinu CG, Ahmedah HT, et al. Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques. Toxics. 2021; 9(6):119. https://doi.org/10.3390/toxics9060119
Chicago/Turabian StyleKamil, Muhammad, Arifa Fatima, Sami Ullah, Gowhar Ali, Rasool Khan, Naila Ismail, Mughal Qayum, Marius Irimie, Catalina Georgeta Dinu, Hanadi Talal Ahmedah, and et al. 2021. "Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques" Toxics 9, no. 6: 119. https://doi.org/10.3390/toxics9060119
APA StyleKamil, M., Fatima, A., Ullah, S., Ali, G., Khan, R., Ismail, N., Qayum, M., Irimie, M., Dinu, C. G., Ahmedah, H. T., & Cocuz, M. E. (2021). Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques. Toxics, 9(6), 119. https://doi.org/10.3390/toxics9060119