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Open Access Article

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Hepatic Histopathological Alterations induced by L-Arginine and/or Dexamethasone in Adult Male Albino Rats

Marwan T. M. Abofila, Azab Elsayed Azab, Asma Nagib Ali, Adel Salah El Din Zohdy, Ghada Farouk Mohammed, Azza Abdel Monaem Attia

Universal Journal of Gastroenterology and Hepatology 1(1); 10.31586/ujgh.2022.509 - November 04, 2022

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Abstract

The liver is critical organ for metabolic homeostasis and toxic substance clearance and plays an important role in the systemic response to critical illness. Acute panreatitis (AP) progresses with a local production of inflammatory mediators, eventually leading to systemic inflammatory response syndrome. Knowing that almost all pancreatic mediators released from the pancreas to the blood stream may pass through the liver before their dilution in the systemic circulation, it would be reasonable to assume a determinant role of this organ in development of the inflammatory response associated with acute pancreatitis. Objectives: The study aimed to investigate the time courses of the effects of the exogenous glucocorticoids agonist dexamethasone on microscopical changes occurring in the liver of rats used as a model of AP induced by L-Arginine. Materials and Methods: 60 adult male albino rats weighing 150-200 gm were used. They were divided into 3 groups: Control group: Which is also divided into 2 subgroups (a & b) each of animals of the first were IM injected with 0.5ml/100gm B.W saline and those of second were injected by 0.5mg/100gm B.W dexamethasone. L-Arginine group: which received L-Arginine to induce AP. The animals of this group were divided into 3 subgroups a, b and c the animals of which were sacrificed 3 days, 2 weeks and 1 month after L-Arginine injection respectively. Dexamethasone and L-Arginine group: in which the animals were injected with both L-Arginine and dexamethasone. They were also divided into 3 subgroups a, b and c, the animals of which were sacrificed 3 days. 2 weeks, one month after the injection of the drugs. The liver of the scarified animals were dissected out and prepared for microscopical examination. Results: The histopathological changes that occurred in the livers of acute pancreatitis (AP) model animals started in the periphery of the classic hepatic lobules and progressively extended in a centripetal manner to involve all the cells of the lobules in the late period of the experiment. These changes were in the form of ballooning of the hepatocytes, progressive vacuolation of their cytoplasm most propably with fat globules and depletion of the PAS+ve glycogen granules. Injection of dexamethasone in AP model animals did not improve the case, but on the contrary it made the changes more intense, severe, and rapid. One month after injection of L-Arginine and dexamethasone, the hepatocytes all over the hepatic lobules were severely affected. They were markedly ballooned with severely vacuolated cytoplasm which was completely depleted from its PAS +ve glycogen granules, indicating severe fatty degeneration of the liver. Conclusion: From the previous data, it can be concluded that treatment of AP with dexamethasone is caused a late bad effect on the liver, where it causes its late fatty liver changes.

Figure 1. Photomicrographs of sections of the livers of animals of subgroup IA showing the normal control structure of the liver. CV = central vein, P.A. Portal area. Notice the minimal collagenous fibres content in the stroma, especially in portal areas. (P.A) [figure D]. Also moderate content of PAS +ve glycogen granules is appeared in the hepatocytic cytoplasm [figure B]. A - H&E 40, B - H&E 200, C - PAS 400, D - Masson tricome 100.

Figure 2. Photomicrographs of sections of the livers of animals of subgroup IB showing the ballooned hepatocytes with their severely vacuolated cytoplasm (A) which is intensely packed with PAS +ve glycogen granules (B). a - H&E 400, b - PAS 400

Figure 3. A photomicrograph of section of the liver of an animal of subgroup IIA showing the increased ballooning and vacuolation of hepatocytes at the periphery of the hepatic lobules (zone I&II). H&E 200

Figure 4. A photomicrograph of section of the liver of an animal of subgroup IIA showing the hepatocytes of the periphery of the hepatic lobules more depleted and vacuolated with well circumscribed vacuoles compared to the central zone. PAS 200

Figure 5. A photomicrograph of section of the liver of an animal of subgroup IIA showing the minimal content of collagenous fibers stroma. Masson trichome 100

Figure 6. A photomicrograph of section of the liver of an animal of subgroup IIB showing the dilated blood sinusoids and the vacuolated hepatocytes all over the lobules. H&E 200.

Figure 7. A photomicrograph of a section of the liver of an animal of subgroup IIB showing that the hepatocytes are relatively depleted from the PAS +ve granules content and vacuolated with well circumscribed vacuoles. PAS 400

Figure 8. A photomicrograph of section of the liver of an animal of subgroup IIB showing the minimal content of collagenous fibres stroma. Notice a focal area of necrosis (*). Masson trichome 100

Figure 9. Two photomicrographs of sections of the livers of animals of subgroup IIC showing marked ballooning of the hepatocytes and vaculation of their cytoplasm with well circumscribed vacuoles as well depletion of the cytoplasmic PAS +ve glycogen granules specially in the periphery of the hepatic lobules. A – H&E 200, B – PAS 400.

Figure 10. A photomicrograph of a section of the liver of an animal of subgroup IIC showing mild increase in the collagen fibers content in the stroma compared to the control specially in the portal area. Masson trichome 100

Figure 11. Photomicrographs of sections of the livers of animals of subgroup IIIA showing that the hepatocytes in a wide area of the periphery of the hepatic lobules are ballooned and has deeply stained eccentric nuclei. The cytoplasm is occupied by well circumscribed vacuoles and depleted from its PAS +ve glycogen granules. A: H&E 100, B: H&E 200, C: PAS 400

Figure 12. A photomicrograph of a section in the liver of an animal of subgroup IIIA showing the minimal collagen fibers content in the stroma comparable with the control group. Masson tricome 100

Figure 13. Two photomicrographs of sections of the livers of animals of subgroup IIIB showing the extension of the hepatocytic ballooning, vacuolation and depletion of PAS +ve granules all over the lobules. a - Masson trichome 100, b - PAS 400

Figure 14. Two photomicrographs of sections of the livers of animals of subgroup IIIC showing the severe affection of the hepatocytes all over the hepatic lobules. The cells appear severely ballooned, vacuolated and completely depleted from their PAS +ve granules. A relative increase in collagenous fibrosis of the stroma is appearent. a- Masson trichome 100, b- PAS 100

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5-fluorouracil Improves the Testicular Antioxidant Status and Alleviates Oxidative Stress in Male Albino Rats Treated with Cyclophosphamide

Rabia A M Yahya, Azab Elsayed Azab, Karema El.M.Shkal, Ahmed M. Attia, Mona A. Yehia

World Journal of Cancer and Oncology Research 1(1); 10.31586/wjcor.2022.492 - November 02, 2022

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Abstract

The therapeutic effect of Cyclophosphamide (CPA) is thus attributed to phosphoramide mustard and acrolein leads to the formation of high levels of reactive oxygen species (ROS), which results in decreased antioxidant activity. Excessive production of ROS could also culminate in oxidative stress. Objectives: This study aims to evaluate the effect of sub-lethal dose of the cyclophosphamide, 5-FU, combination of 5-FU, and CPA on testicular antioxidant status, and oxidative stress in male albino rats. Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=5 each group). Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood and testes tissue samples were taken and prepared for biochemical measurements. Biochemical parameters in rat serum and tissues were evaluated. Results: Individual injection of CPA and 5-FU to rats were reduced testes TAC, GSH concentration, GR, and CAT activities compared to control. However, the combination treatment of rats with 5-FU and CPA increased the levels of these non-enzymatic and enzymatic antioxidant compared with those treated with CPA alone. Also, results showed significantly increased TBARS and NO concentration in the testes of CPA treated rats when compared to normal ones, while 5-FU increased NO only compared with the control. Conclusion: It can be concluded that treatment of rats with CPA is associated with the production of free radicals that leads to hazardous alterations in certain non-enzymatic, and enzymatic functions. The increase in lipid peroxidation probably leads to the intracellular accumulation of ROS with the subsequent development of testes tissue injury. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to combat oxidative stress mediated non target organs injury even if it was not a complete protection. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism.

Figure 1. Testis total antioxidant (U/g tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 2. Testes glutathione (U/g tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 3. Testes glutathione reductase (U/g tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 4. Testes catalase (U/tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 5. Testes TBARS (U/g tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 6. Testes nitric oxide (U/g tissue) of rat treated with cyclophosphamide, fluorouracil and their combination. Significance at P > 0.05. CPA: cyclophosphamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

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Cyclophosphamide Induces Hepatorenal Toxicity and Attenuation by 5-fluorouracil in Male Albino Rats

Rabia A M Yahya, Ahmed M. Attia, Mona A. Yehia, Azab Elsayed Azab, Karema El.M.Shkal

World Journal of Clinical Medicine Research 2(1); 10.31586/wjcmr.2022.455 - October 14, 2022

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Abstract

Background: Cyclophosphamide (CPA) induces acute inflammation of the urinary bladder, renal damage, and liver damage, thereby limiting its therapeutic use. Objectives: The present study aimed to evaluate the hepatorenal toxicity induced by cyclophosphamide and amelioration by 5-fluorouracil in male albino rats. Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=5 for each group). Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken and prepared for biochemical measurements. Results: Serum total protein, albumin, and globulin concentration significantly reduced in animal groups that received cyclophosphamide. 5-FU and CPA combination reduced the changes in total protein, albumin, and globulin compared to CPA treated group. A significant increase in LDH serum concentration was found in CPA, 5-FU, and their combination-treated animals. The mean values of the combination of chemotherapy were above that in CPA followed by 5-FU treatment. Administration of CPA, 5-FU resulted in a significant increase in serum AST, ALT, ALP, and bilirubin compared to the control. Co-treatment 5-FU with CPA significantly attenuated the increase in serum AST, ALT, ALP, and bilirubin when compared to CPA – treated rats. Compared to controls, urea and creatinine levels were increased in CPA-treated rats, while uric acid was reduced in CPA, 5-FU, and their combination. The changes in urea and creatinine produced by the chemotherapy were restored when rats received CPA in combination with 5-FU. Conclusion: It could be concluded that the treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in biochemical parameters. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to combat oxidative stress-mediated non-target organ injury even if it was not complete protection. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism. Toxicological studies must be performed before using drugs as a combination before application. Further research is required on the toxicological impacts of drugs and pollutants mixtures.

Figure 1. Serum total protein concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 2. Serum albumin concentration of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 3. Serum glonulin concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 4. Serum LDH activity of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 5. Serum ALT activity of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 6. Serum AST activity of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 7. Serum ALP activity of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 8. Serum total bilirubin of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 9. Serum urea concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 10. Serum creatinine concentration of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

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5-Fluorouracil Ameliorates the Hematotoxicity Induced by Cyclophosphamide in Male Albino Rats

Rabia A M Yahya, Azab Elsayed Azab, Ahmed M. Attia, Mona A. Yehia, Karema El.M.Shkal

Universal Journal of Pharmacy and Pharmacology 1(1); 10.31586/ujpp.2022.453 - September 27, 2022

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Abstract

Background: Cyclophosphamide (CPA) is a drug with a wide spectrum of clinical uses. Its effectiveness in the treatment of cancer (acute and chronic leukemias, lymphoma, and multiple myeloma) and non-malignant diseases such as rheumatoid arthritis and vasculitis has been well established. Objectives: The present investigation aimed to study the effect of a sub-lethal dose of the cyclophosphamide, 5-FU combination of 5-FU, and CPA on haematological parameters in the albino rats. Materials and Methods: Twenty-eight male adults were grouped randomly into four groups (n=5 in each group). Group I (control): Rats were injected with saline intraperitoneally at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken for hematological evaluation. Results: White blood cells, hemoglobin content and red blood cell counts were significantly decline in rats treated with individual treatment with CPA and 5-FU in comparison to the control group, while the Combination antagonize the changes produced by CPA in hemoglobin and red blood cell counts. Intraperitoneal individual treatment with CPA and 5-FU in rats caused a significant reduction in the hematocrit and platelet. The reductions in these measured hematological parameters were also significantly and slightly ameliorated when the animals were given a combination of CPA and 5-FU. Cyclophosphamide and 5-FU individually reduced lymphocytes, neutrophils, eosinophils, and monocytes; while the combination of CPA and 5-FU antagonized these changes compared to CPA treated group. Conclusion: It could be concluded that the treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in hematological parameters. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism. Using cyclophosphamide and 5-fluorouracil in combination may reduce cyclophosphamide’s side effects when given individually.

Figure 1. WBCs count (x103/µL) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups.

Figure 2. RBCs count (106/µL) of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 3. Hemoglobin content (g/dl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 4. Hematocrit value (%) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 5. Platelets count (103/μl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 6. Lymphocytes count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 7. Neutrophils count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 8. Eosinophils count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 9. Monocytes count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

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