Protective Effects of Caffeic Acid Phenethyl Ester on Isoniazid and Rifampicin-induced Hepatic and Pancreatic Injury

ABSTRACT Objective: To investigate the protective effects of caffeic acid phenethyl ester (CAPE) against isoniazid (INH)- and rifampicin (RFP)-induced hepatic and pancreatic damage. Methods: Eighty adult rats were randomly divided into eight groups: control, INH, RFP, INH+RFP, INH+CAPE, RFP+CAPE, INH+RFP+CAPE, and CAPE. Both INH and RFP were orally administered for 30 days at a dose of 50 mg/kg/day. Caffeic acid phenethyl ester was intraperitoneally injected for 30 days (10 μmol/kg). Blood samples, hepatic and pancreatic tissues were obtained on day 30. Results: Total oxidant status levels were significantly higher in INH and/or RFP-treated groups than those of control and CAPE groups, while total antioxidant status and paraoxonase levels were significantly reduced in INH-RFP groups compared with the group receiving CAPE. Histopathological deterioration was observed in RFP and INH groups in pancreatic and hepatic tissue. However, significant amelioration was observed in CAPE-treated groups. Conclusion: Our findings suggest that CAPE may be a promising agent to prevent the side effects of INH and RFP treatment on hepatic and pancreatic tissues.

Detection of borderline dosage of malathion intoxication in a rat's brain.

OBJECTIVE: Humans and other animals are liable to expose to low doses of malathion (MAL). However, experimental studies on its toxic threshold dose and toxic low-dose effects have not been conducted. The aims of this study were to detect the initiation of the toxic effects of sub-acute low doses (2.5, 5, and 10 mg/kg) of MAL by immunohistochemical and biochemical parameters in rat brain. MATERIALS AND METHODS: Twenty-eight rats were randomly assigned into four groups (n=7) including control and three different amounts of MAL-exposed groups (2.5, 5, and 10 mg/kg). RESULTS: On immunohistochemical examination, the number of caspase-3-positive cells in all MAL-exposed groups was significantly higher than in the control group. Consistent with this, the total antioxidant capacity, total oxidant status, and the levels of superoxide dismutase, malondialdehyde, and paraoxanase activity were significantly different in the 5 and 10 mg/kg MAL-exposed groups compared with the control group. Additionally, the total oxidant status and malondialdehyde levels were significantly higher in the 5 and 10 mg/kg MAL-exposed groups compared with those in the 2.5 mg/kg MAL-exposed group. CONCLUSIONS: Our results indicate that over 5 mg/kg MAL exposure may result in dose-dependent oxidative stress, increased caspase-3 activity, and launching to the toxic effects in rat brain.

The effects of caffeic acid phenethyl ester (CAPE) on bacterial translocation and inflammatory response in an experimental intestinal obstruction model in rats.

OBJECTIVE: Intestinal obstruction (IO) is a disease which generates approximately 20% of emergency surgery and tends to with high mortality. Prevention of oxidative stress, bacterial translocation and tissue damage caused by IO is an important medical issue. Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory, antioxidant, anti-bacterial and immunomodulatory agent. In this experimental study, we aimed to investigate the effects of CAPE on bacterial translocation, inflammatory response, oxidative stress and tissue injury caused by intestinal obstruction in a rat model. MATERIALS AND METHODS: Breafly, thirty Wistar albino rats divided into three groups as Sham (n=10), IO (n=10) and IO + CAPE (10 µmol/kg day, intraperitoneal) (n=10). The tissues from the study groups were examined biochemically, microbiologically and histopathologically. RESULTS: In CAPE treated group, decreased serum levels of proinflammatory cytokines (TNF-α, IL-6, IL-1ß) and CRP (p < 0.05), additionally increased serum levels of antioxidant parameters (PONS, TAS) (p < 0.05), were observed after IO. Microbiologically, the rates of positive cultures of the lymph node, spleen, liver and blood were significantly decreased in CAPE treated group compared to the IO group. Also histopathological examination showed that the intestinal mucosal injury score and hepatic portal inflammation score were significantly decreased in the CAPE treated group (p < 0.05). CONCLUSIONS: It is suggested that intraperitoneal administration of CAPE might has potential antibacterial, anti-inflammatory, antioxidant and immunomodulatory effects in IO. So, further studies on IO are needed to evaluate exact antibacterial, antiinflammatory, antioxidant and immunomodulatory effects of CAPE.

Assesment the role of oxidative stress and efficacy of caffeic acid phenethyl ester (CAPE) on neurotoxicity induced by isoniazid and ethambutol in a rat model.

OBJECTIVE: The aim of this study were to investigate a role of oxidative stress and the therapeutic efficacy of caffeic acid phenethyl ester (CAPE) in the pathogenesis of neurotoxicity induced by isoniazid and etambutol in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into eight experimental groups: control, INH, ETM, INH+ETM, INH+CAPE, ETM+CAPE, INH+ETM+CAPE, and CAPE treatment group, with ten animals in each group. INH and ETM doses were given orally within tap water for 30 days. CAPE was administered into relevant groups intraperitoneally for 30 days. Brain tissue and sciatic nerve were removed for biochemical and histopathological investigation. RESULTS: In the INH, ETM, and INH+ETM groups, malondialdehyde (MDA) and total oxidant status (TOS) levels were significantly higher than those of the control group (p < 0.05). Also, in these groups, brain total antioxidant capacity (TAC) levels, and superoxide dismutase (SOD) and PON-1 activities were decreased compared with the control group (p < 0.05). By a CAPE supplement within INH and ETM groups, there was a significant decrease in MDA and TOS (p < 0.05). In addition to a significant increase in TAC levels, and SOD and PON-1 activities both in brain and sciatic nerve tissues (p < 0.05). CONCLUSIONS: CAPE may protect against INH- and ETM-induced neurotoxicity in rat brain and sciatic nerve.

The effect of bevacizumab and 5-Fluorouracil combination on epidural fibrosis in a rat laminectomy model.

OBJECTIVE: An animal model of laminectomy in rats was used to study scar tissue formation around the spinal cord. Bevacizumab (BV) [a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor], 5-Fluorouracil (5-FU) and BV+5-FU was tested in this system for its ability to decrease fibrous tissue formation. MATERIALS AND METHODS: Twenty-eight Sprague Dawley rats were used in this sudy. Rats were divided into four groups; a control group, a BV group, a 5-FU group and a BV+5-FU group. L1-2 laminectomies were performed on the rats. The medicated groups were treated with topical drug administration. After 6 weeks, the rats were sacrified and histologic sections prepared from the spines were examined and graded by a pathologist. Epidural fibrosis and fibroblast density were evaluated under light microscope. RESULTS: BV (Avastin: Genentech, San Francisco, CA, USA) significantly reduced the density of the scar tissue undermining the laminas (p < 0.005). Monotherapy with 5-FU did not change the scar formation in the back (p = 0.317). Combination of 5-FU and BV was more effective on reducing the epidural fibrosis after laminectomy on rats (p < 0.001). CONCLUSIONS: Bevacizumab reduced the spinal epidural fibrosis significantly that developed in rats after laminectomy and 5-Fluorouracil combination had a synergic effect. Further investigations under the light of these findings may help to reduce epidural fibrosis formation after laminectomy.

The protective effect of ellagic acid on lung damage caused by experimental obstructive jaundice model.

AIM: This study aimed to investigate protective effects of ellagic acid on lungs in an experimental obstructive jaundice model. METHODS: Four groups were established, each consisting of ten randomly selected rats: Group 1: sham, Group 2: ellagic acid, Group 3: obstructive jaundice, and Group 4: obstructive jaundice + ellagic acid. Ellagic acid was administered orally at a dose of 60 mg/kg/day to group 2 and 4. The animals were sacrificed eight days later. The total oxidative status and the total antioxidant capacity in their lung tissue were determined, and malondialdehyde levels in their blood were measured. Histopathological changes in the lungs were examined. RESULTS: In the obstructive jaundice group treated with ellagic acid, there was a decrease in malondialdehyde levels and a reduction in the total oxidative status and the oxidative stress index, whereas the total antioxidant capacity increased (p < 0.001). The histopathological examination showed that neutrophil leukocyte infiltration and edema formation decreased and destruction of lung parenchyma disappeared following the treatment with the ellagic acid (p < 0.05). CONCLUSION: This study shows that ellagic acid has a protective effect against oxidative damage in lung tissue in obstructive jaundice.

The effects of pomegranate on bacterial translocation in rats with obstructive jaundice.

BACKGROUND: Obstructive jaundice may promote bacterial overgrowth and altered intestinal barrier function, with resultant increased bacterial translocation. AIMS: This study aimed to evaluate potential effects of pomegranate on bacterial translocation after bile duct ligation in rats. MATERIALS AND METHODS: Wistar albino rats were randomized into four groups. Group 1 underwent sham operation; Group 2 underwent sham operation and simultaneous treatment with pomegranate; Group 3 underwent common bile duct ligation, and Group 4 underwent common bile duct ligation and simultaneous treatment with pomegranate. After 8 days, the samples of systemic blood, liver, spleen and mesenteric lymph nodes (MLNs) were obtained under sterile conditions for microbiological culture. The segments of the ileum were removed for histopathological examination. RESULTS: Bacterial translocation significantly decreased in Group 4 compared to Group 3 (p = 0.007). The bacterial counts (Colony forming unit: CFU/g) of Group 3 were significantly higher than those of Groups 1, 2 and 4 (p < 0.05). The mean ileal villus heights in the Groups 1, 2, 3 and 4 were 480.5±20.5 µm, 494.7±17.3 µm, 356.3±25.7 µm and 420.7±23.7 µm, respectively. The mean villus height in Group 4 was higher than that of Group 3 (p = 0.010). CONCLUSIONS: Pomegranate has significant protective effects on intestinal mucosa barrier in obstructive jaundice and reduces bacterial translocation.  

The effects of curcumin on the liver and remote organs after hepatic ischemia reperfusion injury formed with Pringle manoeuvre in rats.

BACKGROUND: We aimed to investigate the effects of curcumin on ischemia/ reperfusion (IR) injury of the liver and distant organs resulting from liver blood flow arrest. MATERIALS AND METHODS: Totally 40 rats, divided into four groups, each included 10 rats were used. Group I as only laparatomy, Group II laparatomy and curcumin application, Group III hepatic IR; and Group IV as hepatic IR and curcumin application group. Ischemia was generated by hepatoduedonal ligament clamping for 30 minutes and then reperfusion is started. Curcumin capsules were opened and appropriate dose had been created within weighing scales. After calculations, the powder was diluted with saline. Fifteen minutes before the ischemia, curcumin was applied via oral gavage. Blood samples were taken from the animals for biochemical analysis at 60th minutes of the experiment in the first and second groups; 30 minutes after beginning reperfusion in the third and forth groups. Simultaneously, liver, lung and kidney tissues were sampled for biochemical and histopathological examinations. RESULTS: Plasma malondialdehyde levels were found to be higher (p < 0.001), but total antioxidant activity values were not different in IR group compared with IR + curcumin group (p > 0.05). Biochemical and histopathological evaluation of tissue samples revealed that there were no differences in total antioxidant activity, total oxidant activity and histopathologic scores in IR + curcumin group compared with values of IR group (p > 0.05). CONCLUSIONS: Curcumin did not reduce the effects of hepatic ischemia reperfusion injury on the liver and distant organs including kidneys and lungs significantly.

The effects of ellagic acid on the liver and remote organs' oxidative stress and structure after hepatic ischemia reperfusion injury caused by pringle maneuver in rats.

INTRODUCTION: We aimed to investigate the possible protective effects of ellagic acid (EA) on the liver and remote organs against the hepatic ischemia-reperfusion injury. METHODS: Forty Wistar-Albino rats were divided into four groups each containing 10 rats. Group I with laparotomy only, Group II with laparatomy and ellagic acid application, Group III with hepatic ischemia-reperfusion and Group IV with hepatic ischemia-reperfusion and ellagic acid application. Hepatic ischemia was induced by pringle's manoeuvre for 30 minutes followed by 30 minutes reperfusion period. After induction of ischemia, EA was applied via oral gavage at a dose of 85 mg/kg. Blood samples were taken from the animals for biochemical analysis at 60th minute of the experiment in all groups. Simultaneously, liver, lung and kidney tissues were sampled for biochemical analyses and histopathological examinations. RESULTS: The administration of EA reduced serum malonyldialdehid levels (p<0.05) and liver's oxidative stress index compared with the non-use EA groups (p0.05). The use of EA did not exert significant protective effects against the effects of liver ischemia-reperfusion injury on the kidney and lung. CONCLUSION: In our experiments ellagic acid reduced the liver oxidative stress induced by ischemia-reperfusion injury. However, no significant histological improvement was found with EA. There were no significant protective effects on the remote organ injuries induced by ischemia-reperfusion (Tab. 3, Fig. 7, Ref. 37).

Contribution of low-molecular weight heparin addition to concomitant chemoradiotherapy in the treatment of glioblastoma multiforme.

PURPOSE: Glioblastoma multiforme (GBM) is the most common brain tumor in adults and has a very aggressive course. Median survival is as short as 2 years with standard treatment (chemoradiotherapy followed by adjuvant temozolomide). The purpose of this study was to determine the contribution of low molecular weight heparin (LMWH) addition to concomitant chemoradiotherapy in the treatment of GBM. METHODS: All patients with newly diagnosed GBM between March 2004-May 2009 were evaluated. After surgical intervention (total, subtotal resection or only biopsy) all of them were treated with concomitant chemoradiotherapy (2 Gy daily, 5 days a week, 30 fractions, total tumor dose 60 Gy; and 75 mg/m² temozolomide, 7 days a week), followed by adjuvant temozolomide (6 cycles, 150-200 mg/m², 5 days every 28 days), with or without LMWH (4000 IU/day, 7 days a week, concomitant with radiotherapy) because of risk of thrombosis. The primary endpoint was the determination of progression-free survival (PFS) and overall survival (OS); secondary endpoints were 1- and 2-year OS survival. RESULTS: 30 patients (13 patients in the group non receiving LMWH (LMWH-) and 17 patients in the group receiving LMWH (LMWH+)) were included in the study. Median age was 54 years (range 24-75). Median PFS was 57 and 38 weeks in LMWH+ and LMWH- groups, respectively (p=0.068). Median OS was 69 and 44 weeks (p=0.095), 1-year OS survival 84.6 and 41.2% (p=0.016), and 2-year OS survival 38.5 and 5.9% in LMWH+ and LMWH-, respectively (p=0.061). No significant difference was noted between the two groups for grade 3-4 toxicity (p>0.05). CONCLUSION: Better PFS, OS and 2-year OS survival were obtained in present study with the addition of LMWH to concomitant chemoradiation for GBM but without statistical significance. One-year OS survival was statistically significant favoring the LMWH group. The addition of LMWH did not increase temozolomide toxicity.