ABSTRACT
The synthesis and biological evaluation of eleven derivatives of the natural polyether ionophore monensin A (MON), modified at the C-26 position, is presented. Eight urethane and three ester derivatives were tested for their antimicrobial activity against different strains of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. In addition, their antiparasitic activity was also evaluated with bloodstream forms of Trypanosoma brucei. The majority of the modified ionophores were active against a variety of Gram-positive bacterial strains, including methicillin-resistant S. epidermidis, and showed better antibacterial activity than the unmodified MON. The phenyl urethane derivative of MON exhibited the most promising antibacterial activity of all tested compounds, with minimal inhibitory concentration values of 0.25-0.50 µg/ml. In contrast, none of the MON derivatives displayed higher antitrypanosomal activity than the unmodified ionophore.
Subject(s)
Anti-Bacterial Agents/pharmacology , Monensin/pharmacology , Trypanocidal Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Microbial Sensitivity Tests , Molecular Structure , Monensin/analogs & derivatives , Monensin/chemistry , Parasitic Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanosoma brucei brucei/drug effectsABSTRACT
Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods' growth, when applied at the amount of 4 µg/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 µg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.
Subject(s)
Anti-Bacterial Agents , Staphylococcus epidermidis/growth & development , Tetrazoles/chemistry , Thiourea/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacologyABSTRACT
Natural polyether ionophore salinomycin (Sal) has been widely used in veterinary medicine as an antibiotic effective in the treatment of coccidian protozoa and Gram-positive bacteria. Moreover, chemical modification of the Sal structure has been found to be a promising strategy to generate semisynthetic analogs with biological activity profiles improved relative to those of the native compound. In this context, we synthesized and thoroughly evaluated the antibacterial potential of a library of C1/C20 singly and doubly modified derivatives of C20-epi-salinomycin, that is, analogs of Sal with inversed stereochemistry at the C20 position. Among the synthesized analog structures, the most promising antibacterial active agents were those obtained via regioselective O-acylation of C20-epi-hydroxyl, particularly esters 7, 9, and 11. Such C20 singly modified compounds showed excellent inhibitory activity against planktonic staphylococci, both standard and clinical strains, and revealed potential in preventing the formation of bacterial biofilms. In combination with their non-genotoxic properties, these Sal derivatives represent attractive candidates for further antimicrobial drug development.
Subject(s)
Pyrans , Staphylococcus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cell Line, Tumor , Pyrans/chemistry , Pyrans/pharmacologyABSTRACT
Many helminths cause long-lasting infections, living for several years in mammalian hosts reflecting a well balanced coexistence between host and parasite. There are many possible explanations as to how they can survive for lengthy periods. One possibility is their antioxidant systems, which can serve as defence mechanisms against host-generated oxygen radicals. Therefore, the aim of this experimental study was to examine the antioxidant system in Hymenolepisdiminuta during short (1.5 months young tapeworms) and long (1.5 years old tapeworms) term infection in the rat small intestine. The strobilae of H. diminuta tapeworms (14 young and three old) were divided into three pieces: the anterior part, containing the genital primordiae in the immature segments; the medial part, containing the early uterus in the mature, hermaphroditic proglottids and the terminal part with the mature gravid uterus in the gravid segments. Supernatants of these fragments were used for determination of markers of oxidative stress: concentration of thiobarbiturate reactive substances (TBARS) and of reduced glutathione (GSH), and the activity of antioxidant enzymes: superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidases (GSHPxs), glutathione transferase (GST) and glutathione reductase (GSHR). The results indicated changes in levels of oxidative stress markers and antioxidant enzyme activity in both the young and old forms of H. diminuta. Relatively high activity of SOD (particularly in the anterior part of young tapeworms) was observed, as was increased activity of total GSHPx and a relatively high concentration of GSH in all parts of the tapeworms. These are caused by exposure to increased amount of ROS, which are produced during the inflammatory state. Due to the high activity of antioxidant enzymes, the anterior section of young and old tapeworms is equipped with a very effective antioxidant system. Old organisms also effectively resist oxidative stress due to reduced levels of lipid peroxidation and the high activity of GST, all of which suggest good adaptation to the hostile environment in the host's intestine.
Subject(s)
Antioxidants/metabolism , Hymenolepiasis/metabolism , Hymenolepis diminuta/metabolism , Intestine, Small/parasitology , Animals , Biomarkers/analysis , Catalase/analysis , Glutathione/analysis , Glutathione Peroxidase/analysis , Glutathione Reductase/analysis , Hymenolepiasis/parasitology , Hymenolepis diminuta/enzymology , Lipid Peroxidation , Male , Malondialdehyde/analysis , Oxidative Stress , Rats , Rats, Inbred Lew , Superoxide Dismutase/analysis , Thiobarbituric Acid Reactive Substances/analysis , Time FactorsABSTRACT
UNLABELLED: Oxygen free radicals and their reactive derivatives participate in formation of chronic inflammation states, which facilitate development of gastrointestinal tract tumors. Oxidative stress is one of the main causes of damage to cell membranes in result of exacerbated lipid peroxidation process. End products of lipid peroxidation (aldehydes, organic peroxides) react with important biological macromolecules such as DNA and proteins, cause changes in cell membrane structure and properties leading to loss of its integrity. Intensification of the lipid peroxidation process is a factor which may also lead to a malfunction in the antioxidant barrier, which further weakens the defense of cells against oxygen free radicals and promotes the onset and development of cancer. The aim of the study was the determination of lipid peroxidation level in gastrointestinal tract tumors (stomach, liver, colon, and colorectal cancer to liver metastases). MATERIAL AND METHODS: Materials for studies were obtained from 150 patients with gastrointestinal tract tumors: 10 with stomach cancer, 30 with malignant and benign liver cancers, 60 with primary colorectal cancer, and 50 with metachronous colorectal cancer liver metastases. We also investigated 25 patients with liver cirrhosis, which was treated as a pre-cancerous condition. In total, 175 patients were examined. Tumor specimens, and normal adjacent tissues (6-7 cm from the edge of the tumor), which served as control tissue in studies, were collected from patients (with their consent) during surgery. Additionally, liver specimens were collected from patients with liver cirrhosis. Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products, which in reaction with tiobarbituric acid (TBA) form colour complex (thiobarbituric acid-reactive substances - TBARS). RESULTS: The study showed the highest concentration of TBARS in benign, and the lowest in malignant liver tumors. Other types of gastrointestinal tumors studied, were characterized by similar levels of lipid peroxidation. TBARS concentration in these tumors was approximately 2-fold higher than in malignant liver tumors and much lower than in benign tumors. In all cancers of the digestive tract with the exception of malignant liver tumors increased level of TBARS was found, comparing with control tissue. The concentration of TBARS in cirrhotic liver was lower than in control. The level of lipid peroxidation in liver cirrhosis and malignant liver tumors was similar. There were no significant differences in TBARS concentration in the tumors of particular sections of the intestine and normal colon. The highest concentration of TBARS was found in G1 grade of colorectal cancer. In subsequent grades of cells differentiation (G2 and G3) its concentration was lower. The highest level of lipid peroxidation, expressed as the concentration of TBARS was found in the I stage of colorectal cancer clinical advancement. The significantly lowest concentration of TBARS was shown for stage II (UICC). CONCLUSIONS: The level of lipid peroxidation in cancerous cells of gastrointestinal tract indicates increased oxidative stress. The changes of lipid peroxidation level--a marker of oxidative stress in gastrointestinal tumors appear to be closely associated with their development stages (liver cirrhosis/malignant liver cancer; colorectal cancer/colorectal cancer liver metastases) and are likely to create such conditions, in which cancerous cells may proliferate, undergo gradual dedifferentiation and malignancy, and generate metastases.
Subject(s)
Gastrointestinal Neoplasms/metabolism , Lipid Peroxidation , Liver Neoplasms/secondary , Adult , Aged , Female , Gastrointestinal Neoplasms/pathology , Humans , Liver Cirrhosis/metabolism , Liver Neoplasms/metabolism , Male , Middle Aged , Oxidative StressABSTRACT
INTRODUCTION: Clinical and experimental studies indicate oxygen free radicals and their reactive derivatives participation in formation of chronic inflammation states, which facilitate gastrointestinal tract tumors development. During malignant changes formation in epithelium of gastrointestinal tract increased oxygen radicals generation initiates lipid peroxidation and DNA and proteins oxidation processes. Final lipid peroxidation products (saturated and unsaturated aldehydes) are highly reactive and characterized by greatly longer half life time than reactive oxygen species and capability to diffuse from places of their formation to distant cell areas. In cells they react with important biological macromolecules such as DNA and proteins causing their structural and functional damages. The effects of changes in cell membranes structure are increase in their permeability, depolarization, decrease of hydrophobicity and inhibition of enzymes, membrane channels and transporters. These changes lead to the loss of cell integrity. STUDY AIM: Determination of lipid peroxidation level in blood serum patients with gastrointestinal tract tumors. MATERIALS AND METHODS: Materials for studies were obtained from 170 patients with gastrointestinal tract tumors: 10 with stomach cancer, 20 with pancreatic cancer, 30 with primary liver cancer, 60 with primary colorectal cancer and 50 with metachronic colorectal cancer liver metastases. Blood was taken from patients 1 day before and 6 days after surgery. Control blood was obtained from 53 healthy blood donors. Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products, which in reaction with tiobarbituric acid (TBA) form colour complex (thiobarbituric acid-reactive substances, TBARS). RESULTS: Higher lipid peroxidation level was observed in pre- and postoperative blood sera patients with gastrointestinal tumors in comparison to serum from healthy blood donors. CONCLUSIONS: Increased lipid peroxidation level in peripheral blood of patients with gastrointestinal tract tumors is evidence of intensive oxidative stress and might indicate impairment of antioxidant defense mechanisms in organism.
Subject(s)
Gastrointestinal Neoplasms/blood , Lipid Peroxidation , Adult , Aged , Aged, 80 and over , Female , Humans , Liver Neoplasms/blood , Liver Neoplasms/secondary , Male , Middle Aged , Postoperative Period , Preoperative PeriodABSTRACT
INTRODUCTION: Since one of the many proposed factors in the pathogenesis of acute and chronic pancreatitis is oxidative stress, the aim of the research was evaluation of antioxidant defense mechanisms, with particular emphasis on the role of reduced glutathione and GSH-dependent enzymes. MATERIAL AND METHODS: The study involved a group of 35 patients with pancreatitis treated at the Clinic of General Surgery and Transplantation Medical University of Warsaw in the period from 2005 to 2007. This group consisted of 20 patients with mild symptoms (edema) of the form of acute pancreatitis and 15 patients with chronic pancreatitis, short duration of the disease. In all patients with acute and chronic pancreatitis qualified for the study were measured in serum markers of oxidative stress: concentrations of reactive thiobarbituric acid (TBARS), which determines the level of lipid peroxidation and reduced levels of glutathione (GSH) and activity of antioxidant enzymes: total glutathione peroxidase (cal. GSHPx), glutathione S-transferase (GST) and glutathione reductase (GSHR). RESULTS: We found increased lipid peroxidation level, decreased level of GSH, and changes in activity of GSH-dependent enzymes in blood serum of patients with acute and chronic pancreatitis, compared to blood serum from healthy persons. CONCLUSIONS: Obtained results indicate participation of oxidative stress in pathogenesis of those diseases, and systemic impairment of antioxidative mechanisms.
Subject(s)
Glutathione Peroxidase/blood , Glutathione Reductase/blood , Glutathione Transferase/blood , Pancreatitis/enzymology , Acute Disease , Adult , Aged , Biomarkers/blood , Female , Humans , Lipid Peroxidation , Male , Middle Aged , Oxidative Stress , Pancreatitis/blood , Pancreatitis, Chronic/blood , Pancreatitis, Chronic/enzymology , Thiobarbiturates/metabolismABSTRACT
OBJECTIVES: Superoxide dismutase (SOD) is a key antioxidant enzyme, responsible for scavenging of superoxide anion - a precursor of all reactive oxygen species (ROS). ROS are implicated in many pathologies, particularly in tumor disease. The aim of our work was to evaluate SOD isoforms' activity and protein level changes in liver tumors. DESIGN AND METHODS: Materials were obtained from patients with liver tumors and with liver cirrhosis diagnosed by routine histopathological examination. Activity and protein level of SOD were determined by means of the Beauchamp and Fridovich assay and by Western blot analysis. RESULTS: Decreased activity of CuZnSOD and MnSOD and distinct differences in SOD isoforms' protein expression in liver cirrhosis were found. Results also showed higher protein level and activity of SOD isoforms in liver malignant tumors than in benign ones. CONCLUSIONS: Malignant tumors have a better antioxidant system than benign ones. Moreover, weakening of antioxidant mechanisms and accumulation of oxidative damage in cirrhotic liver could initiate liver carcinogenesis.
Subject(s)
Adenoma, Liver Cell/enzymology , Carcinoma/enzymology , Liver Neoplasms/enzymology , Superoxide Dismutase/metabolism , Adenoma, Liver Cell/metabolism , Adult , Aged , Carcinoma/metabolism , Female , Humans , Isoenzymes/metabolism , Liver Cirrhosis/enzymology , Liver Cirrhosis/metabolism , Liver Neoplasms/metabolism , Male , Middle Aged , Oxidative Stress/physiology , Precancerous Conditions/enzymology , Precancerous Conditions/metabolismABSTRACT
UNLABELLED: Transcription factors AP-1 and NF-kappaB control important cell processes like proliferation, apoptosis and differentiation. Disturbance of this processes is often a reason of carcinogenesis. Therefore AP-1 and NF-kappaB might have an important role in arising and development of tumors. THE AIM OF THE STUDY: An evaluation of changes of AP-1 and NF-kappaB protein level in selected human alimentary tract tumors. Material and methods. Materials were obtained from patients with alimentary tract tumors (stomach, liver; colon), diagnosed by routine histopathological examination. Normal tissues were taken more than 6-7 cm away from tumor border (histologically examined). Protein level of AP-1 and NF-kappaB was detected by standard Western blotting technique. RESULTS: In all examined alimentary tract tumors (gastric adenocarcinoma, hepatocellular carcinoma, colorectal adenocarcinoma and liver metastases) we observed changes in AP-1 and NF-kappaB protein level comparing with normal tissues. CONCLUSIONS: Changes in AP-1 and NF-kappaB expression indicate, that they are important factors not only in initiation, but also in further development of digestive tract tumors.
Subject(s)
Biomarkers, Tumor/metabolism , Gastrointestinal Neoplasms/metabolism , NF-kappa B/metabolism , Transcription Factor AP-1/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Male , Middle AgedABSTRACT
We investigated glutathione level, activities of selenium independent GSH peroxidase, selenium dependent GSH peroxidase, GSH S-transferase, GSH reductase and the rate of lipid peroxidation expressed as the level of malondialdehyde in liver tissues obtained from patients diagnosed with cirrhosis or hepatocellular carcinoma. GSH level was found to be lower in malignant tissues compared to adjacent normal tissues and it was higher in cancer than in cirrhotic tissue. Non-Se-GSH-Px activity was lower in cancer tissue compared with adjacent normal liver or cirrhotic tissue, while Se-GSH-Px activity in cancer was found to be similar to its activity in cirrhotic tissue and lower compared to control tissue. An increase in GST activity was observed in cirrhotic tissue compared with cancer tissue, whereas the GST activity in cancer was lower than in adjacent normal tissue. The activity of GSH-R was similar in cirrhotic and cancer tissues, but higher in cancer tissue compared to control liver tissue. An increased level of MDA was found in cancer tissue in comparison with control tissue, besides its level was higher in cancer tissue than in cirrhotic tissue. Our results show that the antioxidant system of cirrhosis and hepatocellular carcinoma is severely impaired. This is associated with changes of glutathione level and activities of GSH-dependent enzymes in liver tissue. GSH and enzymes cooperating with it are important factors in the process of liver diseases development.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Glutathione/chemistry , Liver Cirrhosis/metabolism , Liver Neoplasms/metabolism , Adult , Aged , Female , Glutathione Peroxidase/metabolism , Glutathione Transferase/metabolism , Humans , Lipid Peroxidation , Male , Malondialdehyde/metabolism , Middle AgedABSTRACT
The aim of our studies was the estimation of activities of antioxidant enzymes in patients with liver cirrhosis. We investigated activities of superoxide dismutases (CuZnSOD, MnSOD), catalase (CAT), selenium dependent GSH peroxidase (Se-GSH-Px), selenium independent GSH peroxidase (non-Se-GSH-Px), GSH-S-transferase (GST), GSH reductase (GSHR) and the level ofreduced gutathione (GSH) in cirrhotic and healthy liver tissues. The activities of CuZnSOD, MnSOD, CAT and GSH-dependent enzymes (except GSHR) were found to be lower in cirrhotic tissue compared to healthy liver. Those changes were associated with decrease of GSH level in cirrhotic tissue compared with control liver tissue. Our results show that antioxidant barrier in liver cirrhosis is impaired. It is associated with decrease of glutathione level and changes of activities of antioxidant enzymes (SOD, CAT, GSHPx, GST, GSHR) in liver cirrhosis compared with healthy liver.
Subject(s)
Antioxidants/analysis , Liver Cirrhosis/enzymology , Liver Cirrhosis/surgery , Liver/enzymology , Adult , Catalase/metabolism , Female , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Glutathione Transferase/metabolism , Humans , Liver/pathology , Liver/physiology , Liver/surgery , Liver Cirrhosis/pathology , Male , Middle Aged , Oxidative Stress , Reference Values , Superoxide Dismutase/metabolismABSTRACT
UNLABELLED: Gastric carcinoma is one of the most common malignancies of causes of cancer death world-wide, although its incidence and mortality and decreasing, particularly in developed countries. One of the many factors in its etiopathogenesis are free oxygen radicals and their derivatives, excess of which comes from disturbances of enzymatic and nonenzymatic mechanisms of antioxidant barrier. The aim of this study was the evaluation activities of antioxidant enzymes: superoxide dismutase (CuZnSOD, MnSOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione transferase (GST), glutathione reductase (GSH-R) as well as measurement of glutathione (GSH) and malondialdehyde (MDA) levels both in tissues (cancer and healthy) and in blood serum obtained from patients with gastric cancer. RESULTS: MnSOD and glutathione dependent enzymes (GSH-Px, GST, GSH-R) activities in gastric cancer were found to be higher than those in healthy stomach tissues. In pre- and postoperative blood serum from patients with gastric cancer was observed increase of CAT and GST as well as decrease of CuZnSOD and GSH-Px compared with the blood serum from healthy blood donors (control group). In preoperative blood serum from patients with gastric cancer GSH-R activity was lower than in control serum, whereas in postoperative serum it was higher compared with serum of the control group. Reduced GSH level was found to be lower in gastric cancer than this in healthy stomach tissue, adjacent to the cancer. Its level was also lower in pre- and postoperative blood serum of patients with gastric cancer compared with level in control serum. MDA concentration was found to be much higher in gastric cancer than this in healthy stomach tissue, whereas weren't significant differences between level of MDA in pre- and postoperative blood serum. CONCLUSION: Our results showed that functioning of antioxidant barrier of organism is severely impaired in patients with gastric cancer.
Subject(s)
Antioxidants/metabolism , Stomach Neoplasms/metabolism , Aged , Aged, 80 and over , Case-Control Studies , Catalase/blood , Female , Glutathione/blood , Glutathione Peroxidase/blood , Glutathione Transferase/blood , Humans , Male , Malondialdehyde/blood , Middle Aged , Poland , Statistics, Nonparametric , Stomach Neoplasms/enzymology , Stomach Neoplasms/surgery , Superoxide Dismutase/bloodABSTRACT
In the present work we examined selected parameters of antioxidant status in patients with primary colorectal cancer and liver metastasis of colorectal cancer. Total antioxidant status (TAS), activity of superoxide dismutase (SOD) and catalase (CAT) were examined in colorectal primary cancer, liver metastasis of colorectal cancer and in blood serum of patients before and after surgery. It was found that patients have disordered function of the the antioxidant system. This is demonstrated by decreased TAS and changes in the activity of SOD and CAT, both in tumor tissue and blood serum.
Subject(s)
Adenocarcinoma/metabolism , Antioxidants/metabolism , Catalase/metabolism , Colorectal Neoplasms/metabolism , Liver Neoplasms/metabolism , Superoxide Dismutase/metabolism , Adenocarcinoma/blood , Adenocarcinoma/enzymology , Adenocarcinoma/secondary , Adult , Aged , Case-Control Studies , Catalase/blood , Colorectal Neoplasms/blood , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , Female , Humans , Liver Neoplasms/blood , Liver Neoplasms/enzymology , Liver Neoplasms/secondary , Male , Middle Aged , Superoxide Dismutase/bloodABSTRACT
The mutagenic activity of yuccaols A, B, and C, trans-resveratrol and trans - 3.3',5.5'-tetrahydroxy -4'-methoxystilbene was tested by the Ames method with Salmonella typhimurium strains TA97, TA98, TA100, TA102 in the absence and presence of metabolic activation (S9 fraction). These phenolic compounds have been isolated and identified from the hark of Yucca schidigera. All of them were found to be non-toxic and non-mutagenic for testing doses in any of the S. typhimurium strains.
Subject(s)
Phenols/chemistry , Plant Bark/chemistry , Yucca/chemistry , Animals , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Mutagenicity Tests , Phenols/isolation & purification , Plant Extracts/chemistry , Rats , Rats, Wistar , Salmonella typhimurium/drug effectsABSTRACT
The aim of this work was to evaluate the efficiency of the antioxidant system in patients with primary hepatocellular carcinoma. Total antioxidant status (TAS), superdoxide dismutase (SOD) and catalase (CAT) activity was examined in liver primary cancers and in blood serum of patients before and after surgery. In comparison with healthy liver, very low activity of TAS was observed in liver cirrhosis and in primary cancer. High activity of TAS in the blood serum of patients before and after surgery was comparable with TAS activity in blood serum of healthy persons. The highest activity of SOD and CAT was observed in liver cirrhosis. The lowest activity was observed in liver primary cancer. Activity of SOD and CAT in the blood serum of patients before surgery was higher than in the blood serum of patients after surgery. The highest activity was observed in the blood serum of healthy persons. Obtained results shows, that the dysfunction of the defensive antioxidant mechanisms have characterised with not only local disturbances (in the tumour cells region), but also circuital ones (blood). Low levels of the activity of TAS, SOD and CAT in patients with primary hepatocellular carcinoma indicate to the distortion of the oxidant--antioxidant balance and the decrease of organism antioxidant system efficiency. These observations show at the participation of free radical processes in the tumour pathogenesis.
Subject(s)
Carcinoma, Hepatocellular/enzymology , Catalase/metabolism , Liver Neoplasms/enzymology , Superoxide Dismutase/metabolism , Adult , Aged , Aged, 80 and over , Catalase/blood , Female , Humans , Male , Middle Aged , Superoxide Dismutase/bloodABSTRACT
The aim of the study was an evaluation of changes in protein level and activity of SOD isoenzymes, and the participation of AP-1 and NF-kappaB in subsequent stages of colorectal cancer development. Studies were conducted on 65 colorectal cancers. Controls were unchanged colon regions. Activity of SOD isoenzymes, lipid peroxidation level (TBARS), and protein level of SOD1, SOD2, AP-1 and NF-kappaB were determined. We found that the protein level and activity of SOD isoenzymes and protein level of AP-1 and NF-kappaB change in subsequent stages of clinical advancement of colorectal cancer, according to UICC (I-IV), and in grades of tumor cells differentiation (G(1)-G(3)). These results indicate adaptation of colorectal cancer cells to oxidative stress, and show that the observed changes of SOD activity and protein level depend on gradual progression of colorectal cancer, and suggest an impairment of processes regulated by AP-1 and NF-kappaB which are critical for tumor progression (proliferation, differentiation and apoptosis).
Subject(s)
Colorectal Neoplasms/enzymology , Isoenzymes/genetics , Superoxide Dismutase/genetics , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Lipid Peroxidation/genetics , Male , Middle Aged , NF-kappa B/genetics , Oxidative Stress/genetics , Superoxide Dismutase-1 , Transcription Factor AP-1/geneticsABSTRACT
OBJECTIVES: Glutathione (GSH) and enzymes cooperating with it - glutathione peroxidase (GSHPx), glutathione S-transferase (GST) and glutathione reductase (GSHR) - play crucial role in cell defence against reactive oxygen species (ROS), which are implicated in tumor disease. The aim of this study was to determine if neoplastic diseases of gastrointestinal tract may influence blood GSH level and its dependent enzyme activity. DESIGN AND METHODS: Blood serum was obtained before and after surgery from patients with gastric, liver and colorectal cancers, and colorectal cancer liver metastases. Lipid peroxidation and GSH levels, and GSH-dependent enzyme activities were determined by means of spectrophotometric methods. RESULTS: Increased level of lipid peroxidation and significant differences in GSH level and GSHPx, GST and GSHR activities were observed in serum taken before and after surgery from patients with gastrointestinal tract tumors compared to those in control serum (from healthy blood donors). CONCLUSIONS: Increase of lipid peroxidation and changes in GSH level and related enzyme activities, suggest oxidative stress in serum of patients with gastrointestinal tract tumor causes, which probably arise as a result of enormous production of ROS in the system. These alterations reflect the presence of functional defence mechanism against oxidative stress related firmly to the glutathione metabolism.