Genotoxicity,toxicity, and carcinogenicity of the antihistamine methapyrilene (MTR 07216)

The antihistamine methapyrilene hydrochloride (MP) has been shown to be a potent hepatocarcinogen in rats, but not in hamsters or guinea pigs. This finding is in contrast to the relative nongenotoxicity of this compound. MP has been evaluated for genotoxicity in a wide variety of short-term tests and has generally demonstrated little genotoxic activity. One exception to this is the mouse lymphoma L5178Y mutagenesis assay, in which MP produced a very significant increase in small colony mutants with concomitant chromosomal damage in these cells. MP also induced positive responses in several cell transformation assays. One potentially very significant effect of MP is that it induces a large increase in hepatic cell proliferation coupled with mitochondrial proliferation in the livers of treated animals. This effect is discussed as a possible mechanism of liver tumor induction in rats.     

A comparison of the effects of castration and 6-methylene progesterone, a 5 alpha-reductase inhibitor, on the rat ventral prostate

6-Methylene progesterone (6MP) is an irreversible in vitro kcat inhibitor of rat prostate 5 alpha-reductase, the enzyme which converts testosterone (T) to dihydrotestosterone (DHT). Treatment of adult rats with 6MP or diethylstilbestrol (DES) decreased the weight of the ventral prostate (VP) by 45%, while castration reduced it by 86%. Histologically, the 6MP-treated VP were indistinguishable from those of controls, while the VP from DES-treated rats showed fibrous stromal hypertrophy as in castrated rats. The prostatic hydroxyproline content, an index of collagen levels, was enhanced by castration or DES, but was not significantly increased by 6MP. Within 2 days of 6MP treatment, the 5 alpha-reductase activity was reduced by 46% and ornithine decarboxylase (ODC) activity was lowered by 27%. During this time the prostatic acid phosphatase activity increased 42% and remained elevated with continued exposure to 6MP up to 13 days. The castration-induced involution of the VP was accompanied by a reduction in serum T and an increase in serum luteinizing hormone (LH). 6MP had no effect on T and LH serum levels but reduced the DHT content within the VP by 64%. Our results indicate that the structure and secretory acid phosphatase activity of the VP are less sensitive to changes in the ratio of T:DHT than is cell proliferation. Thus, the relative amounts of DHT and T within the VP may prove to be more significant than the absolute amount of either androgen in controlling prostate growth or its attendant neoplasms.     

Immunohistochemical study of cell proliferation, Bcl-2, p53, and caspase-3 expression on preneoplastic changes induced by cadmium and zinc chloride in the ventral rat prostate.

This work was directed to evaluate immunoexpression of markers for apoptosis, resistance to apoptosis, and cell proliferation, as well as estimates of nuclear size in ventral prostate of rats treated with cadmium chloride and cadmium+zinc chloride because a possible protective effect of zinc has been postulated. The following variables were studied: volume fraction (VF) of Bcl-2 immunostaining, percentage of cells immunoreactive to proliferating cell nuclear antigen (LIPCNA) and p53 (LIp53), numerical density of caspase-3 immunoreactive cells (NV caspase-3), and estimates of volume-weighted mean nuclear volume (upsilonV). The LIPCNA and VF of Bcl-2 were significantly increased in the treated animals. The dysplasias (independent of their origin) showed a significant increase of the LIp53, NV caspase-3, and upsilonV in comparison with normal acini from treated and control animals. It can be concluded that cell proliferation is enhanced in long-term cadmium-exposed rats, and exposure to zinc combined with cadmium had no effect on any of the variables studied when comparing with normal acini. The increase of nuclear upsilonV could indicate a more aggressive behavior for pretumoral lesions.     

Influence of beta-adrenergic antagonists on cell proliferation rates in the kidney of untreated and diethylnitrosamine-treated male F344 rats.

Some nongenotoxic chemicals which cause kidney tumors have been shown to stimulate tubular cell proliferation. The aim of this study was to evaluate the effects of two beta-adrenoreceptor blocking agents, propranolol and atenolol, on cell proliferation rates in the kidneys of male F344 rats. Immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and mitotic index have been examined in formalin-stored kidneys from F344 rats used in an initiation-promotion study of carcinogenesis. Cell proliferation rate was quantified in the proximal tubule epithelium. Non-initiated rats and rats initiated with a single dose of diethylnitrosamine (DEN, 200 mg/kg, i.p.) were continuously treated with propranolol (75-100 mg/kg) or atenolol (300 mg/kg) by gavage and were sacrificed after 2, 4, 8 or 21 months of experimentation. There were two control groups, one untreated (D1) and one given distilled water by gavage (D1). Control group D1 showed significantly lower cell proliferation rates than the D0 group. In non-initiated rats, propranolol had a weak enhancing effect on cell proliferation, most evident after 4 months, while atenolol had a clear enhancing effect most evident after 8 months of promoting regimen. Treatment with DENalone resulted in a significant increase in cell proliferation rate as compared to group D1. In DEN-initiated rats given propranolol, there was a borderline significant increase in cell proliferation rates, compared to rats given DEN alone, after 8 months of promoting regimen. Atenolol had no effect. Because of the differences in body weight gain and food consumption observed among the various groups, it is suggested that the state of nutrition may have obscured the effects of beta-blockers on cell proliferation rates.     

Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats

Thermal injury has been shown to alter gut epithelium and heart myocyte homeostasis by inducing programmed cell death. The effect of thermal injury on hepatocyte apoptosis and proliferation, however, has not been established. The purpose of this study was to determine whether a large thermal injury increases liver cell apoptosis and proliferation and whether these changes were associated with alterations in hepatic nuclear factor kappaB (NF-kappaB) expression and changes in liver enzymes and amount of protein. Sprague-Dawley rats received a 40% total body surface area scald burn or sham burn. Rats were killed and livers were harvested at 1, 2, 5, and 7 days after burn. Liver cell apoptosis was determined by terminal deoxyuridine nick end labeling (TUNEL) assay and cell proliferation by immunohistochemistry for proliferating cell nuclear antigen. Hepatic NF-kappaB expression was determined by Western blot, and total hepatic protein content was determined by protein assay. Protein concentration decreased after burn compared with sham controls (P < 0.05). Liver cell apoptosis, proliferation, and NF-kappaB expression in hepatocytes increased in burned rats compared with controls (P < 0.05). It was concluded that thermal injury induces hepatic cell apoptosis and proliferation associated with an increase in hepatic NF-kappaB expression and a decrease in hepatic protein concentration.     

Effects of diazepam on cell proliferation in cerebral cortex, anterior pituitary and thymus of developing rats

The effect of a single dose (5mg/kg b.w.) of diazepam on the cell proliferation in selected organs of 11-day old female Sprague-Dawley rats has been investigated. The stathmokinetic method (counting of mitoses after colchicine administration) has been used for evaluation of cell replication. The significant fall of the mitotic activity in the parietal cerebral cortex and the anterior pituitary gland was found. On the other hand, the increase of the mitotic activity in thymus was observed. The reported data, taken together with the previous observations from our and other laboratories, suggest the involvement of benzodiazepine receptor in the control of cell proliferation.     

Effect of thyrotropic hormone on the membrane potential of thyroid gland cells and thyroid hormone secretion with aging

Effect of thyrotropic hormone (TTH) on membrane potential (MP) of thyroid cells and thyroid hormone secretion was studied in experiments on male rats of two age groups (7--12- and 27--32-month-old animals). It was found that during the first 3 hours after TTH administration (5 U/100 g i. v.) the depolarization of secretory cell membranes of adult rats was done pronounced and developed more rapidly than in old ones and that an increase in free thyroxin (T4) correlation with MP changes with time. In a dose of 0.5 U/100 g TTH caused a significant rise in T4 secretion only in old rats. The cAMP level in the thyroid gland declined with aging. In a dose of 5 U/100 g TTH provoked a significant increase in the cAMP content in adult rats and had no effect on its content in old ones. A relationship between the MP level of thyroid secretory cells and thyroid hormone secretion is discussed.     

Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones

Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.     

Inhibition of the proliferation of Nb2 cells by femtomolar concentrations of cholera toxin and partial reversal of the effect by 12-O-tetradecanoyl-phorbol-13-acetate

One hour of exposure to cholera toxin is sufficient to elicit a significant delay in the initiation of DNA synthesis and cell division in lactogenic hormone-dependent Nb2-11C lymphoma cells. The inhibitory effect occurs already at very low concentrations of cholera toxin (5-50 fM), at which it is not accompanied by a detectable increase in intracellular cAMP, or ADP-ribosylation of the alpha subunit of Gs, the stimulatory guanine nucleotide binding protein of adenylate cyclase; IBMX, the phosphodiesterase inhibitor, acts synergistically to cholera toxin, indicating that a minute increase in cAMP may be sufficient for the inhibition. This indication is substantiated by the finding that dibutyryl cAMP also inhibits cell proliferation. Phorbol diester reverses partially the inhibitory activity of cholera toxin. It is most likely that this effect does not result from blocking the increase in cAMP, but rather from some subsequent, yet unidentified, events. The inhibitory effect of cholera toxin is not dependent on the concentration of the proliferation-stimulating lactogenic hormone and cannot be abolished or reduced by excess of the hormone. Cholera toxin also inhibits the autonomous proliferation of a lactogenic hormone-independent cell line (Nb2-SP); however, in this case the inhibition is not affected by TPA.     

PDGF-α stimulates intestinal epithelial cell turnover after massive small bowel resection in a rat

Numerous cytokines have been shown to affect epithelial cell differentiation and proliferation through epithelial-mesenchymal interaction. Growing evidence suggests that platelet-derived growth factor (PDGF) signaling is an important mediator of these interactions. The purpose of this study was to evaluate the effect of PDGF-α on enterocyte turnover in a rat model of short bowel syndrome (SBS). Male rats were divided into four groups: Sham rats underwent bowel transection, Sham-PDGF-α rats underwent bowel transection and were treated with PDGF-α, SBS rats underwent a 75% bowel resection, and SBS-PDGF-α rats underwent bowel resection and were treated with PDGF-α. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined at euthanasia. Illumina's Digital Gene Expression analysis was used to determine PDGF-related gene expression profiling. PDGF-α and PDGF-α receptor (PDGFR-α) expression was determined by real-time PCR. Western blotting was used to determine p-ERK, Akt1/2/3, bax, and bcl-2 protein levels. SBS rats demonstrated a significant increase in PDGF-α and PDGFR-α expression in jejunum and ileum compared with sham animals. SBS-PDGF-α rats demonstrated a significant increase in bowel and mucosal weight, villus height, and crypt depth in jejunum and ileum compared with SBS animals. PDGF-α receptor expression in crypts increased in SBS rats (vs. sham) and was accompanied by an increased cell proliferation following PDGF-α administration. A significant decrease in cell apoptosis in this group was correlated with lower bax protein levels. In conclusion, in a rat model of SBS, PDGF-α stimulates enterocyte turnover, which is correlated with upregulated PDGF-α receptor expression in the remaining small intestine.     

Differential gonadotropin releasing hormone (GnRH) expression, autoregulation and effects in two models of rat luteinized ovarian cells

GnRH has been suggested to participate in corpus luteum function. Here we studied the expression of GnRH mRNA and peptide in two models of rat luteinized tissues: ovarian cells from PMSG-hCG treated prepubertal rats (SPO) and from intrasplenic ovarian tumors (Luteoma). A GnRH autoregulatory effect was evaluated as well as its action on cell proliferation and apoptosis. GnRH mRNA was present in SPO, isolated corpora lutea from SPO and Luteoma from 1 week to 7 months of development. In vitro cultures of Luteoma cells expressed 2-fold higher GnRH mRNA and 10-fold higher GnRH peptide than SPO cells. Buserelin (GnRH analog) increased GnRH mRNA and peptide expression in SPO but not in Luteoma cells. While basal proliferation was very low in Luteoma cells, SPO cells showed a significant increase in cell number by both the thymidine and the MTS methods after 72 h in culture. Buserelin induced a decrease in cell number in both cell types to a similar degree. Although basal apoptosis levels were higher in SPO than in Luteoma cells, Buserelin-induced apoptosis was only detected in Luteoma cells after 48 h treatment. These results show that the two types of rat, luteinized tissues, Luteoma and SPO, markedly differed in some intrinsic properties and in their local GnRH systems. Luteoma cells proliferate very weakly, express and secrete high amounts of GnRH, do not show an autoregulatory effect and respond to the decapeptide with apoptosis stimulation. In contrast SPO cells proliferate significantly, secrete low levels of GnRH but possess a positive, autoregulatory mechanism and respond to GnRH stimulation with impairment of proliferation.     

Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane

BACKGROUND: Exemestane is an irreversible steroidal inhibitor of cytochrome‐P450 aromatase required for estrogen synthesis. The safety of the drug in the pediatric population, particularly in males, has not previously been evaluated. Given the increased interest in treating children with aromatase inhibitors, we undertook a study in rats to assess the potential for exemestane to alter reproductive development and function when administered to juveniles. METHODS: Male and female rats were treated with exemestane at doses anticipated to produce exposures approximately 2‐ and 35‐fold the expected clinical plasma exposure in young adult males during the period of reproductive maturation. After maturation, treated rats were mated to evaluate the potential impact on reproductive function. RESULTS AND CONCLUSION: There were no effects on sexual maturation in either sex or on female reproductive function. Treatment of juvenile male rats caused increased cohabitation time and decreased copulation rates; pregnancy rates and litter size were not affected in rats that mated. Decreased testis (10–15%) and epididymis (20–30%) weights, and decreased Sertoli cell numbers were noted at all doses. This indicates that exemestane can reduce Sertoli cell proliferation during maturation. The sensitive window for this effect is expected to be limited to the period of Sertoli cell proliferation, which is completed by around postnatal day 15 in rats and before puberty in humans. Treatment beginning at a later time relative to the window for Sertoli cell proliferation or for a longer duration is not expected to have additional adverse effect as the effect was not shown to be degenerative. Birth Defects Res (Part B) 92:304–313, 2011. © 2011 Wiley‐Liss, Inc.     

Glucose transporters: structure, function, and regulation

Glucose is transported into the cell by facilitated diffusion via a family of structurally related proteins, whose expression is tissue-specific. One of these transporters, GLUT4, is expressed specifically in insulin-sensitive tissues. A possible change in the synthesis and/or in the amount of GLUT4 has therefore been studied in situations associated with an increase or a decrease in the effect of insulin on glucose transport. Chronic hyperinsulinemia in rats produces a hyper-response of white adipose tissue to insulin and resistance in skeletal muscle. The hyper-response of white adipose tissue is associated with an increase in GLUT4 mRNA and protein. In contrast, in skeletal muscle, a decrease in GLUT4 mRNA and a decrease (tibialis) or no change (diaphragm) in GLUT4 protein are measured, suggesting a divergent regulation by insulin of glucose transport and transporters in the 2 tissues. In rodents, brown adipose tissue is very sensitive to insulin. The response of this tissue to insulin is decreased in obese insulin-resistant fa/fa rats. Treatment with a beta-adrenergic agonist increases insulin-stimulated glucose transport, GLUT4 protein and mRNA. The data suggest that transporter synthesis can be modulated in vivo by insulin (muscle, white adipose tissue) or by catecholamines (brown adipose tissue).     

Leptin, cell proliferation and crypt fission in the gastrointestinal tract of intravenously fed rats

Many peptides, hormones and growth factors have been implicated in the control of cell renewal in the gastrointestinal epithelium. Leptin is present in the stomach and salivary glands and leptin receptors are seen throughout the gut. Leptin can stimulate mitogen-activated protein kinase activity in vitro and short-term infusion has been reported to have a proliferative action on the colon in vivo, suggesting a biological link between obesity, physical activity and colon cancer. Food intake is one of the most important determinants of intestinal mucosal cell renewal, thus any direct effects of leptin on the gut may be hidden. This problem has been avoided experimentally by maintaining animals on total parenteral nutrition (TPN). Male Wistar rats were anaesthetized and cannulae were inserted into the jugular vein to deliver the TPN diet to which had been added 0, 0.5, 2.5, or 10 mg/kg of recombinant murine leptin. Orally fed rats were also studied. After 6 days of treatment, all animals were injected with vincristine and killed 2 h later. Tissue weight was recorded and crypt cell proliferation (arrested metaphases) and crypt fission were scored in 'microdissected' crypts. Leptin infusion led to a small decrease in body weight and in the weight of the caecum. Intestinal cell proliferation was significantly reduced by TPN when compared to the orally fed rats, but the addition of leptin had no effect on the small intestine or colon. Crypt fission was also significantly lowered in the TPN group. Fission was slightly but significantly increased in the proximal and mid-colon of the leptin-treated rats, but was decreased in the distal colon. Although leptin did not significantly alter cell proliferation, it had significant effects on the process of crypt fission in the colon, which varied according to the exact locality.     

Aspirin, age, and proximity to lymphoid nodules influence cell proliferation parameters in rat colonic crypts

Recent epidemiological studies have demonstrated a correlation between regular aspirin (acetylsalicylic acid) use and decrease risk for the development of fatal colorectal cancer. An increase in the size of the cell proliferation compartment in colorectal crypts has been correlated with an increased risk for the development of colon cancer in animals and in humans. To determine if acetylsalicylic acid acts to decrease the size of the cell proliferation compartment, young (3 month) and old (22 month) rats were treated intragastrically with: 1 the vehicle for acetylsalicylic acid delivery (0.25% wt/vol carboxymethylcellulose in 0.15 N HCI), 2 a single dose of acetylsalicylic acid (100 mg/kg), or 3 acetylsalicylic acid (30 mg/kg) given daily for 30 days. One day after the last treatment, colons were resected, fixed, sectioned and mounted on slides for immunohistochemical staining with a monoclonal antibody to proliferating cell nuclear antigen to assess cell proliferation parameters in the colonic crypts. The results were subjected to three way analysis of variance to assess the effects of: 1 rat age, 2 acute or chronic acetylsalicylic acid treatment, and 3 location of crypts over and away from aggregates of lymphoid nodules on the crypt proliferative parameters. Results demonstrated that: 1 acetylsalicylic acid treatment caused an overall decrease in the proliferative zone height, as measured in number of cells in the crypt column, 2 that crypts located over aggregates of lymphoid nodules had significantly higher proliferative activity than crypts located away from aggregates of lymphoid nodules, and 3 after chronic acetylsalicylic acid treatment there was a greater suppression of proliferative zone height in the crypts of old rats than in the crypts of young rats. In conclusion, acute and chronic intragastric delivery of acetylsalicylic acid caused an overall downward shift in the cell proliferation compartment of colonic crypts of young and of old rats. Whether or not acetylsalicylic acid administration will cause the same proliferative zone height response in carcinogen-treated rats is not yet established.     

Resveratrol causes cell cycle arrest, decreased collagen synthesis, and apoptosis in rat intestinal smooth muscle cells

One of the most difficult and treatment-resistant complications of Crohn's disease is the development of fibrotic intestinal strictures due to mesenchymal cell hyperplasia and collagen deposition. Resveratrol, a phytoalexin found in berries, peanuts, grapes, and red wine, has been shown to inhibit fibrosis in vasculature, heart, lung, kidney, liver, and esophagus in animal models. Resveratrol has also been shown to inhibit oxidation, inflammation, and cell proliferation and to decrease collagen synthesis in several cell types or animal models. The aim of this study was to determine whether resveratrol has antifibrotic effects on intestinal smooth muscle cells. Responses to resveratrol by cultured smooth muscle cells isolated from colons of untreated Lewis rats were examined; this rat strain is used in a model of Crohn's disease with prominent intestinal fibrosis. A relative decrease in cell numbers following treatment with 50 and 100 μM resveratrol was evident at 24 h (P ≤ 0.005). This effect was largely due to cell cycle arrest, with an increase in the percent of cells in S phase from 8 to 25-35% (P < 0.05). Cell viability was unchanged until 2-3 days of treatment when there was a 1.2- to 5.0-fold increase in the percent of apoptotic cells, depending on the assay (P < 0.05). Expression of collagen type I protein was decreased following treatment with resveratrol for 24 h (to 44 and 25% of control levels with 50 and 100 μM resveratrol, respectively; P < 0.05). Expression of procollagen types I and III mRNA was also decreased with resveratrol treatment. Resveratrol (50 μM) diminished the proliferative response to TGF-β? (P = 0.02) as well as IGF-I-stimulated collagen production (P = 0.02). Thus resveratrol decreases intestinal smooth muscle cell numbers through its effects on cell cycle arrest and apoptosis and also decreases collagen synthesis by the cells. These effects could be useful in preventing the smooth muscle cell hyperplasia and collagen deposition that characterize stricture formation in Crohn's disease.     

Membrane potential of muscle fibers exposed to corticotropin and hydrocortisone]

The effect of a single intraperitoneal administration of corticotropin (1 unit) and hydrocortisone (5 mg) per 100 g of a body weight on the membrane potential (MP) as well as on the response rate of miniature end plate potentials (RRMEPP) of musculus soleus fibres of various polarization levels has been investigated in rats. It is shown that administration of corticotropin does not change the MP value, while that of hydrocortisone elicits its increase at the low initial polarization level of the muscle fibre membrane and its decrease at the high level. Hydrocortisone administration does not change the MP value at normal levels of fibre polarization. Corticotropin having been administered, RRMEPP of fibres both with high MP levels and with low ones has increased. Fibres with normal polarization also show a tendency to increase. Administration of hydrocortisone has induced a substantial increase of RRMEPP in fibres with high polarization levels within 45 min, while PRMEPP of fibres with normal polarization levels increased within first 5 min., and that of fibres with low levels of polarization remained unchanged.     

Immunomodulating action of myelopeptides in severe closed experimental craniocerebral injury in rats

An immunocorrective effect of myelopeptides (MP) isolated from pig bone marrow cell culture supernatant in the early posttraumatic period in rats with severe cranial injury has been assessed. MP administration prevented cellular devastation of thymus and bone marrow, as well as spleen hyperplasia. The most marked MP effect was observed within the first 24 h after its administration. MP affected the functional and migration properties of both the entire population of lymphoid cells and individual subpopulations. MP had a pronounced protective effect against Staph. aureus infection during cranial trauma. MP completely prevented the death of animals and reduced more than 3-fold Staph. aureus persistence in the organism of animals. Anti-stress and protective effects of MP open vast prospects for their therapeutic and preventive application in the clinical practice.     

Naringenin, a flavanone inhibits the proliferation of cerebrally implanted C6 glioma cells in rats

Tumor cells are able to survive and proliferate in spite of their increased oxidative stress. This was taken as a hint for the implication of oxidants/antioxidants in the proliferation of glial-tumor cells. In the present study, an anti-proliferative effect of Naringenin, an antioxidant against cerebrally implanted C6 glioma cells in rats has been investigated. The status of lipid peroxidation/antioxidants, expressions of protein kinase C, nuclear factor κB, cyclin D1, cyclin dependent kinase 4, proliferating cell nuclear antigen, vascular endothelial growth factor, argyophillic nucleolar organizing regions and histopathology of brain tissues of control and experimental rats were analyzed. On supplementation of naringenin (50mg/kg BW for 30 days) to glioma induced rats, there was a reduction in lipid peroxidation with an increased antioxidant status. There was a significant decrease in the expressions of protein kinase C, nuclear factor κB, cyclin D1 and cyclin dependent kinase 4 on naringenin treatment. Further, the drug could modulate the glial-tumor cell proliferation as evidenced from the histopathological findings, argyophillic nucleolar organizing regions staining, proliferating cell nuclear antigen and vascular endothelial growth factor immunostaining. The findings suggest that naringenin could underlie the inhibition of glial tumor cell proliferation in C6 glioma models of rat.     

The localization of Fos B, a member of transcription factor AP-1 family, in rat odontoblasts and pulpal undifferentiated ectomesenchymal cells

It has been proposed that cellular proliferation and differentiation are accomplished by AP-1 components but different components can be responsible for different functions. The aim of this study was to compare the localization of Fos B, which is a component of AP-1, in postmitotic differentiated and undifferentiated cells via Fos B immunoreactivity. For this purpose, maxillary incisor teeth from 10 Wistar rats were obtained and Fos-B was investigated immunohistochemically in formalin-fixed, paraffin-embedded tooth sections containing odontoblasts, which are postmitotic differentiated cells, and pulpal undifferentiated ectomesenchymal cells. No significant differences in percentage of Fos B-positive cells were observed between the two cell types (p>0.05). These findings suggest that Fos B, a component of AP-1 family, seems to have a negligible effect on differentiation and proliferation in odontoblasts and pulpal undifferentiated ectomesenchymal cells.