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Results for “Cell Proliferation”

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PubMedDate not supplied

Angiotensin converting enzyme inhibition in the postnatal rat results in decreased cell proliferation in the renal outer medulla.

1. Chronic angiotensin converting enzyme (ACE) inhibition or AT1 antagonism during postnatal development in the rat has been shown to cause renal tubular and vascular damage, particularly in the outer medulla. 2. The effects of ACE inhibition were investigated at a stage of development before the renal outer medulla is fully established. 3. Sprague-Dawley rat pups were given daily i.p. injections of either enalapril or saline from days 3-10. At day 11, kidneys were perfusion-fixed for either electron microscopy or immunocytochemistry. Sections were incubated in proliferating cell nuclear antigen (PCNA) antisera and the avidin-biotin immunoperoxidase method was used to detect an immunoreactive product, indicative of proliferating cells. 4. Following enalapril treatment, the normal structural arrangement of the outer medulla was disrupted compared with controls. Cell proliferation (PCNA-positive cells) in the medullary rays was reduced in enalapril-treated kidneys compared with control kidneys. 5. Thus, angiotensin II appears to be essential for normal tubular and vascular growth in postnatal renal development in the rat.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

Treadmill exercise increases cell proliferation in dentate gyrus of rats with streptozotocin-induced diabetes.

Diabetes mellitus is a common and serious metabolic disorder in humans. Streptozotocin (STZ)-induced diabetic rats were shown to produce a significant reduction in the number of proliferating cells in the dentate gyrus. In the present study, the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats with STZ-induced diabetes was investigated via immunohistochemistry. Male Sprague-Dawley rats were divided into four groups: the control-rest group, the control-exercise group, the diabetes-rest group, and the diabetes-exercise group. Each of the animals of the diabetes groups was given a single injection of STZ (50 mg/kg) intraperitoneally. All animals were injected with 5-bromo-2'-deoxyuridine (50 mg/kg) for six consecutive days, starting on the second day after STZ injection, and rats of the exercise groups were made to run on treadmill for 30 min each day over the same period. On the eighth day of the experiment, all animals were sacrificed. In the present results, it was shown that cell proliferation in the dentate gyrus is suppressed under diabetic conditions, and that treadmill is effective in enhancing hippocampal granular cell proliferation in rats with STZ-induced diabetes. These results raise the possibility that treadmill exercise is of help in the alleviation of the central neural sequelae of diabetes mellitus.

Animals↗

PubMed1984

T-lymphocyte subsets in human lymph nodes: relative increase of OKT-8+ cells in neoplastic and reactive B-cell proliferation.

Cell suspensions obtained from 54 human lymph nodes involved by different pathological conditions were characterized by conventional markers and by the OKT-3, OKT-4, OKT-8, OKIa-1, and OKM-1 monoclonal antibodies. In 18 cases of reactive lymphoid hyperplasia, the majority of lymph node cells were mature T lymphocytes (E-RFC = 56 +/- 9%; OKT-3+ = 63 +/- 10%); among T-cell subsets, OKT-4+ cells were 49 +/- 8% whereas OKT-8+ cells were 21 +/- 8% (T4/T8 = 2.7 +/- 1.1). This distribution of T-cell phenotypes was not similar in the different histological types of reactive lymphoid hyperplasia. In fact, an increase in the percentage of OKT-8+ cells (25 +/- 9%; P less than 0.05) and a decrease in the values of the T4/T8 ratio (2.1 +/- 1.0; P less than 0.05) were observed in 9 cases of reactive lymphoid hyperplasia of follicular type when they were compared to the mixed and sinus types. In 13 lymph nodes involved by B-cell lymphoma, the percentage of T lymphocytes was markedly reduced (E-RFC = 21 +/- 12%; OKT-3+ = 27 +/- 18%) and the percentage of OKIa-1+ cells (51 +/- 15%) was significantly (P less than 0.01) increased as compared to reactive nodes; in addition, in these cell suspensions, an increase in the relative proportion of OKT-8+ cells (T4/T8 = 1.4 +/- 0.7; P less than 0.01) could also be demonstrated. Finally, a clear prevalence of OKT-4+ cells on OKT-8+ cells was demonstrated in 5 cases of tuberculous lymphadenitis (T4/T8 = 3.9 +/- 1.5; NS) and in 18 cases of Hodgkin's disease (T4/T8 = 4.2 +/- 2.0; P less than 0.01). In tuberculous lymphadenitis, a significant increase (P less than 0.01) in the percentage of OKM-1+ cells could also be demonstrated.

Antibodies, Monoclonal↗

PubMed2005

Characterization of cell proliferation in the adult dentate under normal conditions and after kainate induced seizures using ribonucleotide reductase and BrdU.

Ribonucleotide reductase (RNR), an enzyme for DNA synthesis, was recently used as a marker of proliferating cells in the dentate gyrus and subventricular zone in normal adult mammalian brains. However, the duration of RNR expression in normal adult brain and the expression pattern of RNR in the adult dentate gyrus following brain injury have not been explored. In this study, we examined the duration of the RNR expression in newborn cells in the normal adult rat brain by analysis of RNR and BrdU double-labeled specimens at different time intervals after BrdU application. Secondly, we induced, in adult rats, seizures by kainic acid and investigated the changes in expression of RNR following seizures, and characterized the phenotype of RNR-positive cells using a variety of other markers. Our results revealed that RNR was detectable in proliferating cells from 2 h to at least 1 day. At 7 and 28 days after seizures, there was a fivefold increase in number of clusters of RNR-positive cells in the dentate gyrus, and a doubling of the number of BrdU-labeled cells in each cluster. Proliferating astrocytes and neuronal precursors were recognized in each RNR-positive cell cluster, and both types increased in number after seizures. Colocalization of RNR and activated caspase-3 was observed at 7 days, indicating that proliferating cells were susceptible to status epilepticus induced damage. RNR immunohistochemistry provides a useful approach in experiments investigating a change in cell proliferation, revealing the location, number, morphology and fate of newly formed cells after, e.g., brain injury.

Animals↗

PubMed2004

Cell proliferation and cell cycle control: a mini review.

Tumourigenesis is the result of cell cycle disorganisation, leading to an uncontrolled cellular proliferation. Specific cellular processes-mechanisms that control cell cycle progression and checkpoint traversation through the intermitotic phases are deregulated. Normally, these events are highly conserved due to the existence of conservatory mechanisms and molecules such as cell cycle genes and their products: cyclins, cyclin dependent kinases (Cdks), Cdk inhibitors (CKI) and extra cellular factors (i.e. growth factors). Revolutionary techniques using laser cytometry and commercial software are available to quantify and evaluate cell cycle processes and cellular growth. S-phase fraction measurements, including ploidy values, using histograms and estimation of indices such as the mitotic index and tumour-doubling time indices, provide adequate information to the clinician to evaluate tumour aggressiveness, prognosis and the strategies for radiotherapy and chemotherapy in experimental researches.

Cell Cycle↗

PubMed1994

Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis.

The objective of this study was to quantify the changes in p53 and cyclin D1 protein levels in different stages of human esophageal and gastric cardia carcinogenesis in a high-risk population in Henan, China. Immunoreactivity of p53, cyclin D1 and proliferating-cell nuclear antigen (PCNA) was observed in the cell nuclei of esophageal and gastric cardia biopsies. The number of p53-immunostaining-positive cells was low in normal epithelia, slightly increased in basal-cell hyperplasia (BCH), markedly increased in dysplasia (DYS) (10-fold), and further increased in squamous-cell carcinoma (SCC) (40-fold). This pattern of change was similar to that of cell proliferation as indicated by PCNA immunostaining. On the other hand, the number of cyclin D1-immunostaining-positive cells did not increase from BCH to DYS, although a slight increase from DYS to SCC was noted. In the gastric cardia, again, the pattern of change of p53-positive cells in different stages of lesions paralleled the pattern of cell proliferation. The number of p53-positive cells was very low, much lower than that of PCNA-positive cells, in normal, chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG); therefore, the increase of p53-positive cells from CAG to DYS was more dramatic (100-fold). From DYS to adenocarcinoma (AC), the p53-positive and the PCNA-positive cells increased 4-fold. On the other hand, the number of cyclin D1-positive cells did not increase in pre-cancerous lesions, but increased slightly in AC. This study demonstrates that p53 protein accumulation increased with the progression of pre-cancerous lesions, especially in the genesis of dysplasia, both in the esophagus and in the gastric cardia. Our approach of quantitative immunohistochemistry sheds light on the mechanisms of genesis of esophageal and gastric-cardia cancers, which frequently occur together in many high-incidence areas.

Adenocarcinoma↗

PubMedDate not supplied

Intravenous injection of an immunoconjugate (anti-PSA-IgG conjugated to 5-fluoro-2'-deoxyuridine) selectively inhibits cell proliferation and induces cell death in human prostate cancer cell tumors grown in nude mice.

Current chemotherapeutic and/or endocrine treatments for adenocarcinoma of the prostate are not delivered selectively to prostate cancer cells, therefore, they are used in very high doses that induce many unpleasant side effects in patients. New approaches are, therefore, needed to deliver drugs directly to prostate cancer cells to improve treatment effects. We hypothesized that antibody immunoglobulin G (IgG) against human prostate specific antigen (PSA) (anti-PSA-IgG) could function as a carrier protein for conjugated chemotherapeutic drugs (such as 5-fluoro-2'-deoxyuridine, doxorubicin, etc.) and that the immunoconjugate could be delivered selectively to PSA-producing neoplastic prostate. Immunoconjugate would then preferentially inhibit cell proliferation and induce cell death in PSA-producing tumor cells, but not in non-PSA-producing prostate cancer cells or other solid organs of the host. The short-term treatment effect could be assessed by measuring cell death and cell proliferation in tumor-bearing animals. We tested our hypothesis by intravenously injecting an immunoconjugate (anti-PSA-IgG-5-fu-2'-d) into nude mice with subcutaneous PSA-producing LNCaP or non-PSA-producing Du-145 prostate tumors. During 5 days of treatment, we observed that immunoconjugate was retained preferentially in PSA-producing LNCaP tumors where it produced cytotoxic effects in neoplastic prostate cells as revealed by decreased cell proliferation and increased cell death, but similar effects were not observed in non-PSA-producing Du-145 tumor cells or mouse organs. Analysis of untreated control mouse with LNCaP tumor, anti-PSA-IgG alone, anti-irrelevant-IgG-drug complex, and drug alone treatments indicated that there was little or no cytotoxic effects of these treatments on LNCaP and Du-145 tumors, and host organs. Our analysis of control and experimental data showed that the immunoconjugate was highly specific in imparting cytotoxic effects on LNCaP prostate tumors, but not on Du-145 tumors and mouse organs. Thus, we have shown that the immunoconjugate selectively delivered a chemotherapeutic drug to PSA-producing prostate tumor cells where it produced measurable cytotoxic effects on cell proliferation and cell death. This is the first report to show a successful delivery of a chemotherapeutic drug in the immunoconjugate to PSA-producing LNCaP prostate tumors in nude mice and without inducing cytotoxic effects on mouse organs.

Animals↗

PubMed2004

Cholesteryl butyrate solid lipid nanoparticles as a butyric acid pro-drug: effects on cell proliferation, cell-cycle distribution and c-myc expression in human leukemic cells.

Cholesteryl butyrate solid lipid nanoparticles (chol-but SLN) have been proposed as a pro-drug to deliver butyric acid. We compared the effects on cell growth, cell-cycle distribution and c-myc expression of chol-but SLN and sodium butyrate (Na-but) in the human leukemic cell lines Jurkat, U937 and HL-60. In all the cell lines 0.5 and 1.0 mM chol-but SLN provoked a complete block of cell growth. Cell-cycle analysis demonstrated in Jurkat cells that 0.25 mM chol-but SLN caused a pronounced increase of G2/M cells and a decrease of G0/G1 cells, whereas in U937 and HL-60 cells chol-but SLN led to a dose-dependent increase of G0/G1 cells, with a decrease of G2/M cells. In Jurkat and HL-60 cells 0.5 mM chol-but SLN induced a significant increase of sub-G0/G1 apoptotic cells. Cell growth and cell-cycle distribution were unaffected by the same concentrations of Na-but. A concentration of 0.25 mM chol-but SLN was able to cause a rapid and transient down-regulation of c-myc expression in all the cell lines, whereas 1 mM Na-but caused a slight reduction of c-myc expression only in U937 cells. The results show how chol-but SLN affects the proliferation pattern of both myeloid and lymphoid cells to an extent greater than the natural butyrate.

Apoptosis↗

PubMed1998

Fibroblast growth factor 2 uses PLC-gamma1 for cell proliferation and PI3-kinase for alteration of cell shape and cell proliferation in corneal endothelial cells.

PURPOSE: Fibroblast growth factor 2 (FGF-2) induces endothelial-mesenchymal modulation in corneal endothelial cells, including stimulation of cell proliferation and cell shape change and induction of fibrillar collagen. In the present study, we investigated whether FGF-2 uses distinct signaling pathways for individual biological activities. METHODS: Specific metabolic inhibitors were used to block cell proliferation, while reversion of cellular morphology (modulated with FGF-2) was determined using specific antibodies and inhibitors. Immunocytochemical analysis was performed to identify any changes observed in the cytoskeleton in relation to cell shape. Association of cytoskeleton molecules with phosphatidylinositol 3-kinase was determined using co-precipitation. Cell proliferation was assayed using a colorimetric method for determining the number of viable cells. RESULTS: The fibroblastic morphology induced by FGF-2 reverted to a polygonal shape in cells treated with anti-FGF-2 antibody, anti-phosphatidylinositol 3-kinase antibody, LY294002, and genistein, while anti-phospholipase C gamma1 antibody did not to reverse the modulated cell morphology. Cell proliferation mediated by FGF-2 was blocked by metabolic inhibitors (genistein, LY294002 and wortmannin); genistein inhibited FGF-mediated cell proliferation in a dose-response manner and had a maximum inhibition of 80% at 100 microM, while inhibitors of phosphatidylinositol 3-kinase had less inhibitory effect than did genistein. When cytoskeleton proteins were examined, the characteristic punctated staining profiles of vinculin observed in normal cells were maintained in fibroblastic corneal endothelial cells treated with FGF-2. The inhibitors that cause reversion of cell shape also demonstrated the punctated staining potential. Likewise, the staining profiles of alpha-actinin and smooth muscle alpha-actin were not altered, regardless of cell shape. Filamentous actin and alpha-actinin were co-localized to the cytoskeleton and phosphatidylinositol 3-kinase was associated with the cytoskeleton, regardless of cell shape. CONCLUSIONS: These findings indicate that FGF-2 uses distinct and/or dual signaling pathways for individual biological activities.

Androstadienes↗

PubMed2001

Smooth muscle cell proliferation at the vascular anastomotic stricture in rat aortotomy model.

BACKGROUND: We recently suggested that a rat aortotomy model could be substituted for a vascular anastomotic stricture around a suture line. The aim of this study was to verify such a rat aortotomy model using proliferating cell nuclear antigen (PCNA) immunohistochemistry, which is a sensitive method for detection of proliferating cells in vascular tissue after injury. METHODS: Longitudinal aortotomy was performed in the abdominal aorta of the rat subjects. The rats were sacrificed at 1, 2, 4 and 8 weeks following aortotomy (n=20 in each group). The control rats were sacrificed without aortotomy (n=20). The percentage of the lumen occluded by intimal thickening (I/M ratio) was calculated. All tissues were stained with antibodies against proliferating cell nuclear antigen (PCNA). RESULTS: Values of I/M ratio were 8.5+/-4.4%, 15.6+/-9.5%, 11.8+/-5.5%, 9.6+/-6.2% at 1, 2, 4, 8 weeks following aortotomy in the injured groups and 0.4+/-0.1% in the controls, respectively. Those values in the injured group increased significantly as compared to the controls. There were also significant differences between one week and two weeks following aortotomy. The PCNA labeling index at one week following aortotomy (21.4+/-2.7%) was significantly higher than at two weeks following aortotomy (2.8+/-1.9%). SMCs in the intima at four and eight weeks following aortotomy were completely negative for PCNA. CONCLUSIONS: The experimental rat aortotomy model was determined to be useful in the investigation of intimal thickening around the suture line.

Anastomosis, Surgical↗

PubMed2006

Ethanol exposure decreases cell proliferation and increases apoptosis in rat testes.

Ethanol exposure is known to suppress male reproductive activity in laboratory animals and humans. The present study was designed to evaluate whether chronic ethanol exposure decreases proliferative activity or increases apoptosis in the testes. Ethanol (1.5 g/kg or 3 g/kg i.p., 15% v/v in saline) was administrated to adult male rats for 10 days. Proliferating cell nuclear antigen (PCNA) was used as a proliferative marker. Western blot analysis showed that ethanol administration significantly reduced the level of PCNA. Also, immunoreactivity of PCNA-positive cells in the spermatogonia and primary spermatocytes were decreased by ethanol exposure. However, the number of TUNEL-positive cells was significantly increased in the testicular germ cells of ethanol-treated rats. Moreover, ethanol administration significantly increased the level of activated caspase-3 in testes. In conclusion, our findings suggest that ethanol may partly contribute to the suppression of male reproductive activity through a reduction of cell proliferation and an enhancement of cell death in rat testes.

Animals↗

PubMed2005

Ion channels in cell proliferation and apoptotic cell death.

Cell proliferation and apoptosis are paralleled by altered regulation of ion channels that play an active part in the signaling of those fundamental cellular mechanisms. Cell proliferation must--at some time point--increase cell volume and apoptosis is typically paralleled by cell shrinkage. Cell volume changes require the participation of ion transport across the cell membrane, including appropriate activity of Cl- and K+ channels. Besides regulating cytosolic Cl- activity, osmolyte flux and, thus, cell volume, most Cl- channels allow HCO3- exit and cytosolic acidification, which inhibits cell proliferation and favors apoptosis. K+ exit through K+ channels may decrease intracellular K+ concentration, which in turn favors apoptotic cell death. K+ channel activity further maintains the cell membrane potential, a critical determinant of Ca2+ entry through Ca2+ channels. Cytosolic Ca2+ may trigger mechanisms required for cell proliferation and stimulate enzymes executing apoptosis. The switch between cell proliferation and apoptosis apparently depends on the magnitude and temporal organization of Ca2+ entry and on the functional state of the cell. Due to complex interaction with other signaling pathways, a given ion channel may play a dual role in both cell proliferation and apoptosis. Thus, specific ion channel blockers may abrogate both fundamental cellular mechanisms, depending on cell type, regulatory environment and condition of the cell. Clearly, considerable further experimental effort is required to fully understand the complex interplay between ion channels, cell proliferation and apoptosis.

Animals↗

PubMed1998

Cell proliferation rate and nuclear morphometry in Roberts syndrome.

Roberts syndrome (RS) is a rare autosomal recessive disorder characterized primarily by symmetric reduction anomalies of all limbs, growth retardation and craniofacial abnormalities. Most RS patients are reported to present a typical abnormality of their constitutive heterochromatin, accompanied by abnormal cytological growth characteristics. We present an extremely severe case of an RS fetus, karyotypically documented, with a clinical presentation including growth deficiency, tetraphocomelia, frontal meningocele, craniofacial abnormalities and penile enlargement with hypospadias. Nuclear morphometrical analysis in tissues of various organs revealed a reduced nuclear size in RS as compared to normal controls, and statistically significant differences in morphometric parameters related to the nuclear shape. Immunohistochemical study of the same organs showed a reduced expression of proliferating cell nuclear antigen in the presented case, thus indicating a decreased cell proliferation rate in RS. Our results reconfirm previously reported findings in cultured fibroblasts of RS cases, thereby reinforcing on a histologic level, the hypothesis that reduced cell proliferation may be involved in the growth retardation and the reduction abnormalities observed in RS.

Abnormalities, Multiple↗

PubMed2000

Effect of trihalomethanes on cell proliferation and DNA methylation in female B6C3F1 mouse liver.

Trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) are regulated organic contaminants in chlorinated drinking water. In female B6C3F1 mouse liver, the 4 trihalomethanes have demonstrated carcinogenic activity when administered by oral gavage; however, chloroform was not carcinogenic when administered in drinking water. Female B6C3F1 mice were administered the trihalomethanes for 11 days by gavage at 2 dose levels or in the drinking water at approximately 75% saturation. When administered by gavage, the trihalomethanes were toxic to the liver, increased the liver:body weight (bw) ratio, and increased the proliferating cell nuclear antigen-labeling index (PCNA-LI). Chloroform and bromodichloromethane were the most toxic, and they increased the liver:bw ratio the most, while bromoform and chloroform increased the PCNA-LI the most. When administered in drinking water, the toxicity of the trihalomethanes was similar to their low gavage-dose. Furthermore, only chloroform significantly increased the liver:bw ratio and bromoform and chloroform increased the PCNA-LI. Chloroform and bromodichloromethane decreased the level of 5-methylcytosine in hepatic DNA. Methylation in the promoter region of the c-myc gene was reduced by the trihalomethanes. Chloroform administered by gavage was more efficacious than given in drinking water; the efficacy of the other trihalomethanes did not differ for the 2 routes. Thus, in mouse liver, the trihalomethanes administered by gavage enhanced cell proliferation and decreased the methylation of the c-myc gene, consistent with their carcinogenic activity. Furthermore, the more modest toxicity, enhancement of cell proliferation, and decreased methylation induced by chloroform administered in drinking water correlated with its lack of carcinogenic activity. Hence, the activity of the trihalomethanes was dependent on the rate of delivery, i.e. rapid by oral gavage and more slowly in drinking water.

Animals↗

PubMed1989

Numbers of host "helper" T cells and proliferating cells predict survival in diffuse small-cell lymphomas.

Diffuse small-cell lymphomas of B-lineage comprise a group of immunophenotypically related lymphoid malignancies that display variable clinical aggressiveness. We compared a variety of clinical, pathologic, and immunologic characteristics of 64 B-lineage diffuse small-cell lymphomas to patient survival in an effort to define prognostically relevant subtypes of these neoplasms. Neither clinical parameters nor histological subclassification correlated with patient outcome. In contrast, three immunologic features of these lymphomas showed a statistically significant relationship with actuarial survival. Neoplasms that manifested greater than or equal to 25% Ki-67+ cells (proliferation-associated antigen), less than 25% Leu 4+ cells (pan-T antigen), or less than 15% Leu 3+ cells (helper/inducer T-subset antigen) were associated with significantly decreased patient survival as compared to neoplasms with the reverse phenotype (P = .02, P = .003, P = .0005, respectively). Leu 3 findings were of particular importance in initial biopsies (P = .0007), while the Ki-67 findings were significant regardless of time of biopsy (P = .01 for biopsies at diagnosis and P = .004 for other biopsies). These data indicate that immunologic analysis can demonstrate subsets of diffuse small-cell lymphoma with different biologic potential, and suggest that such analysis be included in the routine work-up of patients with this type of neoplasm.

Adult↗

PubMedDate not supplied

Microvessel density and endothelial cell proliferation after amifostine (Ethyol) administration in vivo.

BACKGROUND: As amifostine is rapidly metabolised by the membrane-bound and capillary alkaline phosphatase to the active metabolite WR-1065, microvessel density in normal and cancer tissue may influence the therapeutic potential of the pro-drug WR-2721. Thus, it is of interest how the administration of amifostine itself alters vascular density. MATERIALS AND METHOD: For this study fertilized eggs were used and 0.05 ml amifostine (25.7 micrograms) was injected into the area vasculosa. As controls untreated area vasculosa were examined as well as eggs treated with 0.05 ml NaCl 0.9%, 48 hr after injection the vascular density was determined by histometrical methods. Applying the LAB method we performed immunohistochemical analysis of the proliferating cell nuclear antigen of endothelial cells. RESULTS: There was a significant (p < 0.001) difference in vascular density with a mean microvessel count of 25.08 (+/- 8.45 SD) vascular intersections/mm2 in the untreated control, 30.40 (+/- 12.84 SD) in the NaCl control and 53.69 (+/- 24.56 SD) in the amifostine treated area. There was also a significant (p < 0.001) difference in endothelial cell proliferation (PCNA) between untreated controls with a mean PCNA positivity of 14.05 (+/- 5.28 SD) and amifostine treated area vasculosa with a mean PCNA positivity of 32.22 (+/- 18.14 SD). CONCLUSION: A single dose administration of 25.7 micrograms amifostine induces endothelial cell proliferation and subsequent neovascularisation in the area vasculosa of the fertilised egg.

Amifostine↗

PubMed2006

Supporting cell proliferation after hair cell injury in mature guinea pig cochlea in vivo.

In cold-blooded animals, lost sensory hair cells can be replaced via a process of regenerative cell proliferation of epithelial supporting cells. In contrast, in mammalian cochlea, receptor (hair) cells are believed to be produced only during embryogenesis; after maturity, sensory or supporting cell proliferation or regeneration are thought to occur neither under normal conditions nor after trauma. Using bromodeoxyuridine (BrdU) as a proliferation marker, we have assessed cell proliferation activity in the mature organ of Corti in the cochlea of young guinea pigs following severe damage to the outer hair cells induced by kanamycin sulfate and ethacrynic acid. Although limited, we have found BrdU-labeled nuclei in the regions of Deiters cells when BrdU is given for 3 days or longer. When BrdU is given for 10 days, at least one labeled nucleus can be observed in the organ of Corti in approximately half of the ears; proliferating cells typically appear as paired daughters, with one nucleus being displaced away from the basement membrane to the position expected of the hair cells. Double-staining with antibodies to cytokeratin, vimentin, and p27 have shown that the BrdU-labeled nuclei are located in cells phenotypically similar to Deiters cells. Most of the uptake of BrdU occurs 3-5 days following ototoxic insult, and the number of BrdU-labeled cells does not decrease until 30 days following insult. These findings indicate that Deiters cells in the mature mammalian cochlea maintain a limited competence to re-enter the cell cycle and proliferate after hair cell injury, and that they can survive at least for 1 month.

Animals↗

PubMedDate not supplied

Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis.

An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin, induces growth arrest and cell death in a wide variety of malignant cells in vitro. We analyzed the effect of lovastatin on myeloid leukemic cell lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among 11 myeloid leukemic cell lines in a dose-dependent manner. In order to address the mechanism of antileukemic effect of lovastatin, cell cycle analysis was attempted in HL-60 cells, showing that lovastatin induced G1 arrest in HL-60 cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were decreased after treatment with lovastatin (10 microM) in a time-dependent manner, but not cyclin D1. In addition, lovastatin increased the protein level of the cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FACS analysis with annexin V staining, which was associated with downregulation of Bcl-2 protein. These results suggest that lovastatin inhibits the proliferation of myeloid leukemic cells via G1 arrest in association with p27 induction and is an effective inducer of apoptosis in HL-60 cells.

Apoptosis↗