The protective effect of pomegranate peel aqueous extract on selenite-induced cataract in rats.

The present study was performed to evaluate the preventive effect of pomegranate peel extract on sodium-induced cataract in rats. Sprague-Dawley suckling male rats were divided into four groups: group C: rats received no treatment, group P: rats received pomegranate peel aqueous extract (PPE) orally, group Se: rats received an injection of sodium selenite, group Se + P: rats received PPE and sodium selenite concomitantly. After 4 weeks, rats were sacrificed, and their lenses were homogenized and evaluated for biochemical parameters and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the Se group, developed cataract with significant lens opacity was observed. Other changes in enzymatic and non-enzymatic antioxidants, oxidative parameters, solubility of proteins, in NO and Ca levels and the electrophoresis pattern of proteins were observed in lenses of the Se group compared to control groups. After the preventive administration of PPE, most of these parameters were normalized due to antioxidant and anti-inflammatory activities of the extract. PRACTICAL APPLICATIONS: Cataract is one of the leading causes of vision impairment among the elderly, and surgery is the major therapeutic step taken to cure it. However, surgery has its limitations and complications. Therefore, prevention of cataract development, especially in high-risk individuals, can be better than cure. Pomegranate peel extract has a high potential to prevent cataract in these people.

The protective effect of Zataria multiflora Boiss essential oil on CCl4 induced liver fibrosis in rats.

Activation of hepatic stellate cells by free radicals is an initial step in the development of liver fibrosis. Zataria multiflora Boiss (ZM) essential oil as a natural product has antioxidant activity and maybe a suitable candidate for treatment or prevention of the disease. Thus, this study aims to evaluate the protective effect of ZM oil in CCl4 induced liver fibrosis. Male rats were divided into 5 groups, group C: control rats; CO: vehicle control group; CE: rats that received essential oil (500 µl/kg); F: fibrosis group, rat were intraperitoneally injected with CCl4 (1 mL/kg); FE: fibrosis rats that received both CCl4 and ZM essential oil as mentioned above. At the end of the 11th week, serum samples and liver tissues were collected for the evaluation of fibrosis markers, liver enzymes, oxidative stress parameters and histopathological studies. The results showed a significant increase in the activity of serum AST, ALT, total bilirubin, TGF-ß1, hyaluronan, and hydroxyproline levels in serum and liver tissues in F group. Also, an abnormality in lipid profile and the existence of oxidative stress was found in serum and liver tissues in F group compared to the control groups. Our study showed that ZM essential oil could ameliorate mentioned parameters. Histopathological examinations confirmed the results of biochemical evaluations.

Effect of chemical modification with carboxymethyl dextran on kinetic and structural properties of L-asparaginase.

l-asparaginase is a chemotherapy agent in the treatment of childhood leukemia. l-asparaginase has several side effects and a short blood half-life in patients. Chemical modification of l-asparaginase can decrease its side effects and improve its pharmacokinetic properties. The aim of this project was twofold: to chemically modify l-asparaginase with carboxymethyl dextran via carbodiimide cross linker, and to evaluate and compare the biochemical and structural properties of the native and modified enzymes. Chemical modification was done at 25 °C, in 0.1 M phosphate buffer, pH 7.2, and in the presence of N-hydroxysuccinimide and carbodiimide. Electrophoresis and free amino groups determination confirmed the chemical modification. Biochemical studies showed that the chemical modification could result in higher specific activity and stability of the modified enzyme. Structural studies further confirmed the chemical modification and revealed conformational changes in the modified enzyme. Taken together, the results showed that chemical modification with carboxymethyl dextran brings about improvement of biochemical properties through several changes in the structural attributes of l-asparaginase and might enhance its applicability in the treatment of childhood leukemia.

Niacin improves maturation and cryo-tolerance of bovine in vitro matured oocytes: An experimental study.

BACKGROUND: Nicotinic acid (niacin) is a broad-spectrum lipid-modifying agent that has potent antioxidant properties and reduces the production of lipid peroxidation. OBJECTIVE: The purpose of the present study was to investigate the maturation, embryo development and cryo-tolerance merit, and levels of malondialdehyde (MDA), total oxidant status, and total antioxidant capacity following the supplementation of bovine oocytes maturation medium with different concentrations of niacin. MATERIALS AND METHODS: Immature cumulus-oocyte complexes were cultured in tissue culture medium-199 maturation media supplemented with 0, 100, 200, and 400 µM niacin under a standard in vitro culture condition. After 24 hr of culture, the nuclear maturation rate was assessed. Then, two groups of immature cumulus-oocyte complexes were cultured in TCM-199 either with or without 400 µM niacin and evaluated for embryo development. Also, matured cumulus-oocyte complexes in both groups were frozen using a standard vitrification procedure. After vitrification, oocytes were warmed in two steps and evaluated for embryo development. In addition, the level of total antioxidant capacity, total oxidant status, and MDA were measured. RESULTS: The results indicated that although the treatment with 400 µM niacin increased in vitro nuclear maturation (87.6±5.3), it did not improved the embryo development to the blastocyst stage. Higher cleavage and blastocyst rates were observed in vitrified oocytes that were cultured with supplemented 400 µM niacin compared to the control group (without niacin) (53.6±2.7 and 10.6±1.6 vs. 46.2±4.1 and 6.3±2.4, respectively). Also, the addition of 400 µM niacin to the maturation media could decrease MDA levels after maturation. CONCLUSION: Niacin could improve the quality of in vitro embryo production (IVP) embryos and tolerance of bovine oocytes to vitrification.

Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and ß-Endorphin Concentrations in the Periaqueductal Gray Area in Rats.

Ghrelin is an endogenous ligand for orphan growth hormone secretagogue receptors. Ghrelin receptors have been found in central nervous system (CNS) areas responsible for pain modulation and transmission. This study investigated the effects of intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin on pain behavioral responses and levels of ß-endorphin (ß-EP) and met-enkephalin (MENK) in the periaqueductal gray area (PAG) during the formalin test in rats. Thirty-five male rats were studied in five groups. Ghrelin was injected into the left lateral ventricle (ICV, 5 µL) or into the ARC (1 µL). After 15 min, formalin (2.5%) was subcutaneously injected into the left hind paw. Behavioral nociceptive scores were recorded for 60 min. MENK and ß-EP were collected by microdialysis in the PAG and determined by high-performance liquid chromatography (HPLC). ICV and ARC injection of ghrelin significantly reduced pain in all phases of the formalin test (p < 0.001). Dialysate concentrations of MENK and ß-EP in the PAG increased in all the phases (p < 0.01). In conclusion, the present study shows that the ARC nucleus and the endogenous opioid system are involved in ghrelin-induced pain modulation.

Therapeutic effect of simvastatin on DMBA-induced breast cancer in mice.

Preclinical studies have shown positive effects of statins against specific cancers. This study aimed to determine the therapeutic effect of simvastatin in 12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer. Female albino mice were divided into two groups, with or without DMBA administration. After tumor appearance, DMBA-treated group was further divided into four groups (D1-D4) as control (D1), treated with simvastatin at 80 and 40 mg/kg/day, orally (D2 and D3) and tamoxifen (50 mg/kg/day, orally) treated group (D4). After 4 weeks, animals were sacrificed, serum samples were collected and tumors were dissected for histopathological study and determination of selected parameters. The tumor marker carcinoma antigen 15-3 (CA15-3), oxidative stress parameters and prostaglandin E2 (PGE2) levels were analyzed in serum and tumors in experimental groups. Tamoxifen and high dose of simvastatin improved parameters of mammary carcinogenesis including mean tumor volume, body weight and percent of mortality as compared to mice with breast tumors without treatment (D1). Additionally, simvastatin usage increased total antioxidant capacity (TAC) level, paraoxonase 1 (PON1) activity in serum and decreased total oxidant status (TOS) and malondialdehyde (MDA) levels in tumors similar to tamoxifen. No significant decrease was found in serum CA 15-3 and tumor PGE2 levels in simvastatin and tamoxifen treated groups as compared to D1 group. These data suggest that simvastatin has anticancer effects which are relatively similar to that of tamoxifen in an animal model of breast cancer.

Mevalonate Pathway and Human Cancers.

Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers. Several mechanisms may be involved in dysregulation of this pathway. They include p53 mutation, a mutation in HMG-CoAR and sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP as its regulator, PKB/Akt activation, decreased AMPK activation, and activation of transcription factors such as: SREBP and HIF-1. Statins as inhibitors of MVA pathway might be useful for cancer prevention and/or treatment through their interactions with essential cellular functions, such as cell proliferation and differentiation. Other inhibitors are also designed for inhibition of this key pathway and their mechanism of action was investigated. In the present review, we will first describe about some inhibitors of MVA, including statins that have been suggested for cancer treatment. We will then discuss about the mechanisms involved in MVA dysregulation, especially in cancer.

Effect of Crocin on Cell Cycle Regulators in N-Nitroso-N-Methylurea-Induced Breast Cancer in Rats.

We previously showed the anticancer effect of crocin, a saffron carotenoid, in both breast and gastric cancers in animal models, but its mechanism of action is not clearly known, yet. In this study, the effect of crocin on cell cycle regulators is investigated. Female Wistar Albino rats were divided into two groups, with or without N-nitroso-N-methylurea (NMU) injection. After tumor formation, each group of rats was divided into two subgroups, receiving crocin or vehicle only. After 5 weeks, the rats were sacrificed and the tumors were retained for pathologic investigation and determination of the parameters. Before crocin treatment, the tumor volumes were 13.27±3.77 and 12.37±1.88, but at the end of the experiment, they were 23.66±8.82 and 11.91±2.27 in the control and crocin-treated groups, respectively. Pathologic investigation indicated the adenocarcinoma induction by NMU. Reverse transcription-polymerase chain reaction and Western blot analysis showed overexpression of cyclin D1 and p21(Cip1) in the NMU-induced breast tumors; however, the expression of both of them suppressed by crocin treatment. The previous studies indicated that crocin induces apoptosis in tumor tissue. In this study, we show that it also suppresses tumor growth and induces cell cycle arrest by downregulation of cyclin D1. In addition, crocin suppressed p21(Cip1) in a p53-dependent manner.

High Expression of Cyclin D1 and p21 in N-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats.

OBJECTIVE: N-nitroso-N-methylurea (NMU) induces breast cancer in rodents, particularly in rats. This model of breast cancer is very similar to human breast cancer. As a continuation of our recent work, we investigated the expressions of cyclin D1 and p21 in NMU-induced breast cancer of Wistar Albino rats. MATERIALS AND METHODS: In this experimental study, mammary carcinoma was induced in female Wistar Albino rats by a new protocol which included the intraperitoneal injection of NMU (50 mg/kg) at 50, 65, and 80 days of the animal's age. The animals were weighed weekly and palpated in order to record the numbers, location, and size of tumors. Subsequently tumor incidence (TI), latency period (LP), and tumor multiplicity (TM) were reported. About four weeks after the tumor size reached 1.5 cm3, rats were sacrificed. Cyclin D1 and p21 expressions in tumors and normal mammary glands from normal rats were measured by reverse-transcription polymerase chain reaction (RT- PCR) and Western blot analysis. Statistical analysis of the data was performed using SPSS software version 16.0. RESULTS: The efficiency of tumor induction was 65%, LP was 150 days, and a TM of 1.43 ± 0.53 per rat was noted. RT-PCR and Western blot data indicated significant (p<0.05) induction of both cyclin D1 and p21 expressions in rat mammary tumors compared with normal tissue from the control group. CONCLUSION: These results indicate an efficient mammary tumor induction protocol for this type of rat, which is accompanied by an increase in cyclin D1 and p21 expressions.