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Öğe Apoptotic effects of dipyrido [3,2-a:2 ',3 '-c] phenazine (dppz) Au(III) complex against diethylnitrosamine/phenobarbital induced experimental hepatocarcinogenesis in rats(Springer, 2014) Tekin, Neslihan; Üstüner, Mehmet Cengiz; Akyüz, Fahrettin; Özbayer, Cansu S.; Aydın, Ozlem; Benkli, Kadriye; Burukoğlu, Dilek; Değirmenci, İrfan; Özden, HilmiWe evaluated the effects of dipyrido [3,2-a:2',3'-c] phenazine (dppz) Au(III) complex ([Au(dppz)Cl-2]Cl) on apoptosis during chemically induced hepatocellular carcinoma. 48 male Spraque-Dawley rats were divided into six groups; group I (control), group II [Dimethyl sulfoxide (DMSO)], group III ([Au(dppz)Cl-2]Cl), group IV [diethylnitrosamine + Phenobabital (DEN + PB)], group V (DEN + PB + [Au(dppz)Cl-2]Cl (2nd week)), and group VI (DEN + PB + [Au(dppz)Cl-2]Cl (7th week). The rats in groups IV through VI were administrated with DEN in a single dose of intraperitoneal 175 mg/kg. After 2 weeks of DEN administration, these groups of rats were given daily PB in a dose of 500 ppm. In group V, after two weeks of DEN administration, [Au(dppz)Cl-2]Cl complex (2 mg/kg) was given once a week by intraperitoneal injection. In the group VI, the rats were given a dose of 2 mg/kg [Au(dppz)Cl-2]Cl complex once a week, 7 weeks after DEN administration. At the end of the study, blood and tissue samples were collected from the rats to determine levels of serum AST, ALT, and LDH, and caspase 3, p53, Bax, Bcl-2 and DNA fragmentation in liver. AST, ALT, LDH, and Bcl-2 levels were higher in group IV, compared to group I, but caspase 3 and p53 levels were lower. In group V, caspase 3, p53, Bax, and DNA fragmentation levels were higher than those of group IV. Caspase 3 and p53 levels increased in group VI compared with group IV. In conclusion, [Au(dppz)Cl-2]Cl complex induced apoptosis by elevating levels of caspase 3, p53, Bax, and DNA fragmentation.Öğe Cytotoxic and apoptotic activities of novel Pd(II) complexes against human leukemia cell lines in vitro(Taylor & Francis, 2017) Tekin, Neslihan; Öztürk, Kamile; Baran, Talat; Kerimoğlu, Barış; Tarhan, Mehtap; Menteş, AyferIn the investigation for alternative chemotherapeutic strategies against leukemia, Pd(II) complexes were synthesized and investigated for cytotoxic and apoptotic properties on two human leukemia cell lines (HL-60 and K562). Pd(II) complexes (Pd-5a and Pd-6a) with 5a and 6a as ligands were synthesized and characterized by H-1-NMR and F-TIR. The cytotoxicity of the compounds was quantified using MTT method. Bax, Bcl-2, and caspase 3 gene expression levels were estimated using RT-qPCR. Here we show that Pd(II) complexes have important cytotoxic activity on human leukemia cell lines. RT-qPCR indicated that Bax and caspase 3 gene expression levels were increased after 24h treatment with Pd-5a and Pd-6a complexes in both HL-60 and K562 cells at some selected dose. Furthermore, Bcl-2 gene expression level decreased after 24h treatment with Pd-5a and Pd-6a complexes in K562 cells at all selected dose. In HL-60 cells, only one selected Pd-5a dose (25 mu M) decreased the gene expression level of Bcl-2. The results obtained in the present investigation indicate that these two newly synthesized Pd(II) complexes have apoptotic effects at appropriate doses through caspase 3 and Bax genes and might represent a novel potentially active agents for the management of human leukemia cell lines.Öğe Effects of acetylsalicylate overdose on lipopolysaccharide-induced lung injury in rats: the role of the VEGF(Turkish Biochem Soc, 2012) Akyüz, Fahrettin; Aydın, Özlem; Aydın, Tayfun; Tekin, Neslihan; Temel, Halide Edip; Burukoğlu, Dilek; Aral, ErinçAim: Vascular endothelial growth factor production is decreased depending on the alveolar epithelial cell damage. Acute over expression of vascular endothelial growth factor in lung tissue contributes to the formation permeability. Excessive doses of acetylsalicylate (ASA) may induce pulmonary edema by increasing pulmonary vascular permeability. In this study, the effects of acetylsalicylate overdoses were evaluated on bronchoalveolar lavage fluid levels of vascular endothelial growth factor in the presence of lipopolysaccharide-induced lung injury in rats. Materials and Methods: Lung injury was induced by intraperitoneal injection of lipopolysaccharide (LPS). Rats were divided into six different sets consisting of 7 rats each for control, ASA-300, ASA-500, LPS, LPS+ASA-300 and LPS+ASA-500 series. ASA, 300 mg and 500 mg/kg doses were given by gavage. Acetylsalicylate was given 24 hours after lipopolysaccharide injection in LPS+ASA groups. Rats were sacrificed 6 hours after acetylsalicylate administration and bronchoalveolar lavage was performed. Results: In bronchoalveolar lavage fluid, vascular endothelial growth factor, matrix metalloproteinase-2 and nitric oxide levels were increased in group of ASA-500, and were decreased in groups of LPS+ASA. In addition, plasma salicylate half-life was prolonged in LPS+ASA groups. Conlusion: Lipopolysaccharide increases the time of being metabolized of acetylsalicylate. The lung tissue damage increases due to vascular endothelial growth factor, matrix metalloproteinase-2 and nitric oxide related mechanisms and recovery period is affected adversely. Also in humans, severe toxic effects on the lung tissue that can be generated by 300 and 500 mg/kg acetylsalicylate doses in rats showed less toxic effect.Öğe Effects of S-allyl cysteine on lung and liver tissue in a rat model of lipopolysaccharide-induced sepsis(Springer, 2015) Bayraktar, Orhan; Tekin, Neslihan; Aydın, Özlem; Akyüz, Fahrettin; Musmul, Ahmet; Burukoğlu, DilekSepsis is characterized by a severe production of reactive oxygen species (ROS) and other radical species with consequent oxidative stress. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which is a potent antioxidant and free radical scavenger. In the present study, the purpose was to explore the anti-inflammatory, antioxidant, and anti-apoptotic actions of SAC on lipopolysaccharide (LPS)-induced sepsis in rats. Thirty-two male Wistar rats were separated into 4 groups. These were control, SAC control, sepsis, and sepsis + SAC-induced groups. Sepsis was induced by administration of LPS (5 mg/kg) into 2 groups. SAC (50 mg/kg) was given orally to SAC control and SAC treatment groups per 12 h during 2 days after intraperitoneal LPS injection. Serum AST, ALT, ALP, and hsCRP levels and liver and lung MPO, NO, and DNA fragmentation levels were evaluated. In sepsis group, elevated levels of ALT, AST, ALP, and hsCRP were observed. The abnormal increases were decreased in sepsis + SAC group compared to sepsis group. In lung tissue, MPO and NO levels were increased in sepsis group compared to the control group. MPO activity and NO levels were decreased by SAC application in sepsis + SAC group compared with sepsis group. In liver tissue, DNA fragmentation was significantly higher in sepsis group than that in the control group. In contrast, a decreased level of DNA fragmentation was noted in sepsis + SAC group when compared with the sepsis group. In conclusion, SAC ameliorates LPS-induced indicators of liver damage and suppresses the discharge of NO and MPO in lung tissue via its antioxidant properties.Öğe Possible regulatory effects of application of alpha lipoic acid and insulin against cadmium exposed diabetic rats(Afyon Kocatepe Üniversitesi, 2018) Kılıç, Neşe; Akyüz, Fahrettin; Tekin, NeslihanObjective: Environmental exposure to the cadmium (Cd), is associated with hyperglycemia and reduced serum insulin. This investigation was planned to assess the effects of Lipoic Acid (LA) and insulin on glycolytic enzymes, liver marker enzymes and lipids in Cd exposed diabetic rats. Material and methods: Male Wistar rats were separated into 7 groups (n=8 in each group). Groups were designed as control, diabetic control, diabetic + CdCl2, diabetic + insulin, diabetic + CdCl2 + insulin, diabetic + CdCl2 + LA, anddiabetic + CdCl2 + insulin + LA groups. Type 1 diabetes was established by intraperitoneal (i.p.) injection of streptozotocin (STZ) (65 mg/kg) into 6 groups. Insulin (4 IU/kg/day) was given subcutaneously (s.c.) to insulin treated groups. CdCl2 (1,2 mg/kg/day) was given s.c. to CdCl2 treated groups. LA (100 mg/kg/day) was given i.p. to LA treated groups. CdCl2, LA, and insulin treatment were started 2 days after intraperitoneal STZ injection and continued for 3 weeks. Serum glucose, AST, ALT, BUN, LDL, HDL, and TG levels and liver hexokinase (HK), pyruvate kinase (PK), whole blood HbA1c level, and Na+/K+ATPase activity were evaluated. Results: In diabetic group, serum glucose, HbA1c, TG, LDL, AST, ALT, ALP, and BUN levels were higher than cont- rol, but HDL was lower. In liver tissue, activities of Na+/ K+ATPase, HK and PK activities were decreased in dia- betic control group. PK, HK and Na+/K+ATPase activities were increased in liver in diabetic+CdCl2 and Diabeti- c+Insulin+CdCl2 groups. An increase was determined in activities of HK, PK, and Na+/K+ATPase in insulin and LA treated groups compared with diabetic control group. Conclusions: These results suggest that application of insulin and LA could be an effective therapeutic intervention against liver injury caused by Cd and STZ.Öğe Posttreatment effects of olea europaea L. Leaf extract on carbon tetrachloride-Induced liver injury and oxidative Stress in rats(Mary Ann Liebert, 2018) Üstüner, Derya; Çolak, Emine; Dinçer, Murat; Tekin, Neslihan; Dönmez, Dilek Burukoğlu; Akyüz, Fahrettin; Çolak, Ertuğrul; Kolaç, Umut Kerem; Entok, Emre; Üstüner, Mehmet CengizThe aim of this study is to examine the therapeutic effects of Olea europaea L. leaf extract on carbon tetrachloride (CCl4)-induced liver damage in rats. In the experiments, 3- to 4-month-old 28 male Sprague-Dawley rats were divided into four groups: control, O. europaea leaf extract, CCl4, and curative. The CCl4 and curative groups received CCl4 (0.2mL/kg) intraperitoneally for 10 days to form hepatic injury. O. europaea (80mg/kg) leaf extract was given orally to the curative group dissolved in distilled water the following 14 days. Hepatic and antioxidant enzyme levels, p53, caspase 3, lipid peroxidation marker malondialdehyde (MDA), and also DNA fragmentation levels were determined to establish oxidative stress in hepatic cell damage and its consequences. After formation of liver damage, oral administration of the O. europaea significantly reduced CCl4-induced elevations of serum alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase levels (P<.001), MDA levels of both blood (P<.001) and liver tissues (P<.001), DNA fragmentation (P<.001), p53 (P<.001), and caspase 3 (P<.001) levels of liver tissues. Also this administration in curative group significantly increased CCl4-induced reductions of superoxide dismutase (SOD) (P<.001) and catalase (CAT) (P<.001) activity of blood samples and decreased SOD (P<.001) and CAT (P<.05) activity observed in liver tissue curative groups compared with CCl4 curative group. In CCl4 group, liver tissue samples exhibited remarkable damage because of CCl4 and reduction of these damages were observed in the curative group. Our results showed that O. europaea leaf extract was effective in reducing hepatic damage caused by CCl4 by reducing lipid peroxidation, regulating antioxidant enzymes, and minimizing DNA damage.Öğe Propolis protects endotoxin induced acute lung and liver inflammation through attenuating inflammatory responses and oxidative stress(Mary Ann Liebert, 2018) Yangi, Berat; Üstüner, Mehmet Cengiz; Dinçer, Murat; Özbayer, Cansu; Tekin, Neslihan; Üstüner, Derya; Çolak, Emine; Kolaç, Umut Kerem; Entok, EmrePropolis is a natural bee product, and it has many effects, including antioxidant, anti-inflammatory, antihepatotoxic, and anticancer activity. In this study, we aimed to explore the potential in vivo anti-inflammatory, antioxidant, and antiapoptotic properties of propolis extract on lipopolysaccharide (LPS)-induced inflammation in rats. Forty-two, 3- to 4-month-old male Sprague Dawley rats were used in six groups. LPS (1mg/kg) was administered intraperitoneally to rats in inflammation, inflammation + propolis30, and inflammation+propolis90 groups. Thirty milligram/kilogram and 90mg/kg of propolis were given orally 24 h after LPS injection. After the determination of the inflammation in lung and liver tissues by F-18-fluoro-deoxy-d-glucose-positron emission tomography ((18)FDG-PET), samples were collected. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO), and DNA fragmentation were determined. The decrease of MDA levels in inflammation + propolis30 and inflammation + propolis90 groups was determined compared to the inflammation group in lung and liver tissues. The increase of SOD% inhibition in inflammation + propolis90 group was determined in liver, lung, and hemolysate compared to the inflammation group. Increased CAT activities in inflammation + propolis30 and inflammation + propolis90 groups were observed in liver tissue and hemolysate compared to inflammation group. In lung tissue, NO levels were lower in inflammation group compared to the control group, but DNA fragmentation levels were higher. F-18-FDG uptake of tissues in inflammation + propolis30 and inflammation + propolis90 groups was decreased compared to the inflammation group. In conclusion, the data of this study indicate that the propolis application may serve as a potential approach for treating inflammatory diseases through the effect of reducing inflammation and free oxygen radical production.Öğe Protective effect of curcumin on carbapenem-resistant Escherichia coli-induced lung injury in rats(College of Surgeons, 2016) Bali, Çağla; Altıntaş, Nejat; Özmete, Özlem; Gelincik, İbrahim; Yabanoğlu, Hakan; Tekin, Neslihan; Altınsoy, Bülent; Turan, Bünyamin Cüneyt; Arıboğan, AnısCurcumin has remarkable anti-inflammatory and antioxidant properties. The aim of this study was to investigate the protective effects of curcumin on a rat model of carbapenemresistant Escherichia coli-induced acute lung injury (ALI). Thirty-two rats were randomly allocated to 4 groups to induce an ALI: negative control group (rats not infected with E coli with no antibiotic treatment), positive control group (rats infected with E coli with no antibiotic treatment), imipenem group (rats infected with E coli that received intraperitoneal injection of imipenem), and the imipenem+curcumin group (rats infected with E coli that received intraperitoneal injection of imipenem and were fed on curcumin). The rats were killed, and lung tissues samples were harvested for biochemical analyses and histopathologic examination. Total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL6) were measured. TOS increased in the positive control group (P < 0.001) and decreased in the imipenem and imipenem+curcumin groups (P < 0.001 and P < 0.001, respectively). TAS decreased in the positive control group (P = 0.005). Imipenem treatment did not increase TAS, but the imipenem+curcumin group increased TAS (P = 0.014). TNF alpha and IL6 increased in the positive control group compared with the negative control group (P < 0.001 and P = 0.010, respectively). Imipenem decreased TNF alpha (P < 0.001), but did not decrease IL6 (P = 0.418). Imipenem+curcumin decreased TNF alpha (P < 0.001); this decrease was more pronounced compared with the imipenem group (P = 0.008). IL6 decreased in the curcumin group compared with the positive control group (P = 0.011). Curcumin combined with imipenem can be an alternative therapeutic agent to overcome the resistance of E coli strains.Öğe Role of oxidative stress in pseudoexfoliation syndrome and pseudoexfoliation glaucoma(TURKISH OPHTHALMOLOGICAL SOC, 2019) Yaz, Yasemin Aydın; Yıldırım, Nilgün; Yaz, Yetkin; Tekin, Neslihan; İnal, Mine; Şahin, Fezan MutluObjectives: To investigate the role of oxidative stress on pseudoexfoliation formation and progression from pseudoexfoliation syndrome (XFS) to pseudoexfoliation glaucoma (XFG). Materials and Methods: This study investigated oxidative stress biomarkers in blood samples from 58 patients with XFG, 47 patients with XFS, and 134 healthy age- and sex-matched controls. Results: The highest serum malondialdehyde (MDA) levels were measured in XFG patients (p<0.001), and MDA level was higher in XFS patients than controls (p < 0.001). Superoxide dismutase (SOD) and catalase (CAT) enzyme activities were significantly lower in XFS and XFG patients than in the control group, whereas a significant increase was observed in glutathione (GSII) levels (p<0.001 for all). However, levels of these three biomarkers did not differ significantly between XFS and XFG patients (p=0.188, p= 0.185, and p= 0.733, respectively). Nitric oxide (NO) concentration was significantly lower in XFG patients compared to XFS patients and controls (p<0.001) but did not differ between XFS patients and controls (p= 0.476). Conclusion: Elevated MDA levels suggest that lipid peroxidation is important in XFS and XFG development and progression from XFS to XFG. In addition, reduction in SOD and CAT enzyme activities is considered a deficiency in the enzymatic antioxidant protection system. Furthermore, GSH values may be evaluated as a compensatory response to oxidative stress in XFS and XFG. Alterations in NO indicate the role of a vascular regulatory factor in the progression from XFS to glaucoma.Öğe Serum nerve growth factor (NGF) levels in children with attention deficit/hyperactivity disorder (ADHD)(Elsevier Ltd., 2014) Guney, Esra; Ceylan, Mehmet Fatih; Kara, Mehmet; Tekin, Neslihan; Göker, Zeynep; Şenses Dinç, Gülser; Öztürk, Önder; Eker, Sevda; Kızılgün, MuratAttention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder of childhood. The etiopathogeny of ADHD has not been totally defined. Recent reports have suggested a pathophysiological role of neurotrophins in ADHD. In this study, we evaluated serum levels of nerve growth factor (NGF) in patients with ADHD. The sample population consisted of 44 child or adolescent patients diagnosed with ADHD according to DSM-IV criteria; 36 healthy subjects were included in the study as controls. Venous blood samples were collected, and NGF levels were measured. The mean serum NGF levels of the ADHD patients were significantly higher than those of the controls. Age and gender of the patients were not correlated with serum NGF levels. There were no significant differences in NGF levels among the combined and predominantly inattentive subtypes of ADHD. Our study suggests that there are higher levels of serum NGF in drug naive ADHD patients, and that increased levels of NGF might have an important role in the pathophysiology of ADHD.Öğe The anti-inflammatory and antioxidant effects of salvia officinalis on lipopolysaccharide-induced inflammation in rats(Mary Ann Liebert, Inc, 2017) Kolaç, Umut Kerem; Üstüner, Mehmet Cengiz; Tekin, Neslihan; Üstüner, Derya; Çolak, Emine; Entok, EmreSalvia officinalis, which has a high phenolic acid and flavonoid content, is a powerful antioxidant and anti-inflammatory herb. Inflammation plays an important role in the pathophysiology of many diseases and could cause damage by means of oxidative stress. The aim of this study was to investigate the anti-inflammatory and antioxidant activity of S. officinalis formed lipopolysaccharide (LPS)-induced experimental inflammation model. Four- to five-month-old 42 female Wistar albino rats were divided into six groups. Three groups were administered intraperitoneally 1mg/kg LPS. Twenty-four hours after injection of LPS, 10 and 30mg/kg S. officinalis extract were given orally to treatment groups. Pulmonary and hepatic F-18-fluoro-deoxy-D-glucose (F-18-FDG) uptake was calculated to determine the status of inflammation by 18F-fluoro-deoxy-D-glucose-positron emission tomography ((18)FDG-PET) scan. Antioxidant enzyme activities and nitric oxide (NO) and malondialdehyde (MDA) levels were determined. Nuclear factor-kappa B (NF-B) and tumor necrosis factor-alpha (TNF-) levels were also detected in serum. As a result, lung and liver F-18-FDG uptake was found to be higher in the inflammation group than control group. MDA levels in erythrocyte and all tissue samples (liver, lung, and kidney) were found to be significantly higher compared to treatment groups. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities of the inflammation group in the liver, lung, kidney tissues, and erythrocyte SOD and CAT activities were determined to significantly lower than groups treated with S. officinalis. Increased NO, NF-B, and TNF- levels were found in the inflammation group. S. officinalis has been observed to have useful effects on LPS-induced inflammation and oxidative stress in rats.Öğe The effects of S-Allyl cysteıne on inflammatory cascade in lipopolysaccharide induced rat sepsis model(Eskişehir Osmangazi Üniversitesi, 2021) Tekin, Neslihan; Kolaç, Umut Kerem; Tanrıkut, Cihan; Üstüner, M. Cengiz; Entok, Emre; Akyüz, Fahrettin; Alataş, İbrahim ÖzkanLipopolysaccharide (LPS) is a main constituent of Gram-negative bacterial cell walls and is considered a leading cause of sepsis. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which has a potent antioxidant and free radical scavenger activity. The purpose of this study is to examine the antioxidant and anti-inflammatory potential of SAC on endotoxin LPS-induced sepsis. Female Wistar albino rats were divided into 6 groups. LPS (5 mg/kg) was applied to rats in sepsis and treatment groups intraperitoneally. After 24 hours from LPS injection 50 mg/kg and 100 mg/kg SAC was orally administrated to treatment groups. Lung and liver 18F-fluoro-deoxy-D-glucose (18F-FDG) uptake was measured by 18FDG-PET scan. Serum levels of nuclear factor-kappa B (NF-??), tumor necrosis factor-alpha (TNF-?), matrix metalloproteinase-9 (MMP-9), plasma levels of interleukin-1? (IL-1?), IL-6 and tissue levels of oxidative stress markers catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were determined. As a result of the study, MDA and NO levels of sepsis group were significantly higher than treatment groups in lung tissue. SOD activities of sepsis group was determined to significantly lower in the liver and lung tissues than the groups which were treated with SAC. Likewise, it was concluded that serum MMP-9, TNF-? and NF-?? levels of sepsis group was significantly higher compared to levels of treatment groups. It was determined that SAC administration reduced 18F-FDG uptake in septic rats. In conclusion, SAC was observed to diminish effects of the acute toxicity and oxidative stress formed with LPS.Öğe The hepatocurative effects of Cynara scolymus L. leaf extract on carbon tetrachloride-induced oxidative stress and hepatic injury in rats(Springer International Publishing, 2016) Çolak, Emine; Üstüner, Mehmet Cengiz; Tekin, Neslihan; Çolak, Ertuğrul; Burukoğlu, Dilek; Değirmenci, İrfan; Güneş, Hasan VeysiCynara scolymus is a pharmacologically important medicinal plant containing phenolic acids and flavonoids. Experimental studies indicate antioxidant and hepatoprotective effects of C. scolymus but there have been no studies about therapeutic effects of liver diseases yet. In the present study, hepatocurative effects of C. scolymus leaf extract on carbon tetrachloride (CCl4)-induced oxidative stress and hepatic injury in rats were investigated by serum hepatic enzyme levels, oxidative stress indicator (malondialdehyde-MDA), endogenous antioxidants, DNA fragmentation, p53, caspase 3 and histopathology. Animals were divided into six groups: control, olive oil, CCl4, C. scolymus leaf extract, recovery and curative. CCl4 was administered at a dose of 0.2 mL/kg twice daily on CCl4, recovery and curative groups. Cynara scolymus extract was given orally for 2 weeks at a dose of 1.5 g/kg after CCl4 application on the curative group. Significant decrease of serum alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels were determined in the curative group. MDA levels were significantly lower in the curative group. Significant increase of superoxide dismutase (SOD) and catalase (CAT) activity in the curative group was determined. In the curative group, C. scolymus leaf extract application caused the DNA % fragmentation, p53 and caspase 3 levels of liver tissues towards the normal range. Our results indicated that C. scolymus leaf extract has hepatocurative effects of on CCl4-induced oxidative stress and hepatic injury by reducing lipid peroxidation, providing affected antioxidant systems towards the normal range. It also had positive effects on the pathway of the regulatory mechanism allowing repair of DNA damage on CCl4-induced hepatotoxicity.
