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Biomedical subjects

H Naora

Publications and source records attributed to H Naora.

At least 19 recordsLinked to original sources
PubMed2002

Fine reconstruction of the pancreatic ductular system at the onset of pancreatitis.

The three-dimensional structure of the pancreatic ductular system (from the intercalated duct to the intercellular secretory canaliculus) is controversial and unclear. The aim of this study is to reveal the three-dimensional structure of the pancreatic ductular sysytem at the onset of pancreatitis. One day following rat pancreatic duct ligation, dilated lumina from the pancreatic ductular system were reconstructed by light microscopic and scanning electron microscopic examination of pancreatic tissue serial sections. The existence of the intra-acinar duct, which is formed only by centroacinar cells and interconnects the adjacent central lumina in an acinus, was demonstrated. The intercellular secretory canaliculi, which are the terminal parts of the pancreatic ductular system, anastomose and end blindly in the intercellular space located between adjacent lateral surfaces of the acinar cells. The intercalated ducts, the intra-acinar ducts, the central lumina, and the intercellular secretory canaliculi are arranged together in a complex connecting and branching system. However, there were no anastomoses found among the central lumina or acini.

Animals↗
PubMed2001

Aberrant expression of homeobox gene HOXA7 is associated with müllerian-like differentiation of epithelial ovarian tumors and the generation of a specific autologous antibody response.

Autologous serum antibodies to molecules that are aberrantly expressed in tumors represent potential biomarkers for early diagnosis of cancer. In this study, we identified the homeobox gene HOXA7 as encoding an antigen in epithelial tumors of the ovary. These tumors are thought to arise from the simple epithelium lining the ovarian surface, but they often resemble the specialized epithelia derived from the müllerian ducts. Expression of HOXA7 was detected in ovarian tumors exhibiting müllerian-like features and correlated with the generation of anti-HOXA7 antibodies by patients. In contrast, it was observed that healthy women lack anti-HOXA7 antibodies (P < 0.0001) and that HOXA7 expression is absent from normal ovarian surface epithelium. Interestingly, HOXA7 expression was detected in the müllerian-like epithelium lining inclusion cysts in normal ovaries and in the müllerian duct-derived epithelium of normal fallopian tubes. Furthermore, ectopic expression of HOXA7 enhanced the epithelial phenotype of immortalized ovarian surface epithelial cells, as indicated by the appearance of cobblestone morphology, induction of E-cadherin expression, and down-regulation of vimentin. These findings associate aberrant HOXA7 expression with the müllerian-like differentiation of epithelial ovarian tumors and suggest diagnostic utility of serum antibodies to HOXA7.

Antibodies, Neoplasm↗
PubMed2001

A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells.

Ovarian carcinomas are thought to arise from cells of the ovarian surface epithelium by mechanisms that are poorly understood. Molecules associated with neoplasia are potentially immunogenic, but few ovarian tumor antigens have been identified. Because ovarian carcinomas can elicit humoral responses in patients, we searched for novel tumor antigens by immunoscreening a cDNA expression library with ovarian cancer patient serum. Seven clones corresponding to the homeobox gene HOXB7 were isolated. ELISAs using purified recombinant HOXB7 protein revealed significant serologic reactivity to HOXB7 in 13 of 39 ovarian cancer patients and in only one of 29 healthy women (P < 0.0001). Ovarian carcinomas were found to express HOXB7 at markedly higher levels than normal ovarian surface epithelium, suggesting that immunogenicity of HOXB7 in patients could be associated with its elevated expression in ovarian carcinomas. Overexpression of HOXB7 in immortalized normal ovarian surface epithelial cells dramatically enhanced cellular proliferation. Furthermore, HOXB7 overexpression increased intracellular accumulation and secretion of basic fibroblast growth factor, a potent angiogenic and mitogenic factor. These results reveal HOXB7 as a tumor antigen whose up-regulated expression could play a significant role in promoting growth and development of ovarian carcinomas.

Antigens, Neoplasm↗
PubMed2001

Effects of hyaluronic acid and basic fibroblast growth factor on motility of chondrocytes and synovial cells in culture.

The capacity of chondrogenic precursor cells to migrate and proliferate in an injured area is considered to be essential for cartilage repair. We examined cell motility of chondrocytes and synovial cells in monolayer culture and the chemokinetic effects of hyaluronic acid (HA) and basic fibroblast growth factors (bFGF) on these cells. The velocity of chondrocyte migration was accelerated by giving bFGF and simultaneously administering of both HA and bFGF, but it was not affected by HA alone. The velocity of synovial cell migration was increased by HA, but not by bFGF. HA had a chemokinetic effect on synovial cells and bFGF had the same effect on chondrocytes. Treatment with exogenous HA and bFGF may be of value for repairing articular cartilage injury by recruiting chondrogenic cells and promoting migration of chondrocytes in the cartilage tissue.

Animals↗
PubMed2000

Expression of the long form of leptin receptor (Ob-Rb) mRNA in the brain of mouse embryos and newborn mice.

The long form of the leptin receptor (Ob-Rb) has a cytoplasmic domain which activates the JAK-STAT signal transduction pathway. It is related to appetite and energy expenditure and is expressed in various parts of the brain in adults. In embryos, however, the detailed distribution of Ob-Rb expression sites and the function of the leptin-Ob-Rb system remain unclear, although leptin is detected in human cord plasma and leptin mRNA is detected in mouse embryos. In this study, we investigated the Ob-Rb mRNA expression pattern in the brains of mouse embryos and newborn mice by RT-PCR and in situ hybridization. At embryonic day 10.5 (E10.5), Ob-Rb mRNA was already detected in the brain by RT-PCR. By in situ hybridization, Ob-Rb mRNA was observed in the ventricular zone of the rhombencephalon at E11.5. At E12.5, it was also expressed in the ventricular zone of the telencephalon, mesencephalon and cerebellar primordium. From E14. 5 it was expressed in the cortical plate of the telencephalon and the ventricular zone of the thalamus. At E16.5, it was expressed in the premamillary hypothalamic nucleus, superficial gray matter of the superior colliculus, external germinal and Purkinje cell layers of the cerebellum, and facial nucleus. At E18.5, it was expressed in the arcuate nucleus and ventromedial hypothalamic nucleus. These results suggest that the leptin-Ob-Rb system is related to brain development.

Animals↗
PubMed2000

HIV, cytokines and programmed cell death. A subtle interplay.

HIV infection is marked by the progressive destruction of the CD4 T lymphocyte subset, an essential component of the immune system and a vital source of cytokines required for differentiation of natural killer (NK) and gamma delta T cells, for maturation of B lymphocytes into plasmocytes, and for differentiation of CD8+ T cells into virus-specific cytotoxic T lymphocytes. CD4 T lymphocytes are also a source of chemokines which control migration of lymphocytes to the site of infection and which also inhibit HIV entry into CD4-expressing targets. Continuous production of viral proteins leads to an unbalanced immune activation and to the triggering of apoptotic programs, turning mononuclear cells, including CD4 T cells, CD8 T cells and APC, into effectors of apoptosis, leading to fratricidal destruction of healthy uninfected cells expressing the death receptors. Inappropriate PCD is also responsible for the disappearance of T helper cells primed for type-1 cytokine synthesis, thus contributing to the lack of survival factors which could prevent spontaneous lymphocyte apoptosis. Under potent anti-retroviral therapies, a significant decrease in spontaneous, TCR- and CD95-induced lymphocyte apoptosis is observed, concomitant with a partial quantitative and qualitative restoration of the immune system in treated patients. However, owing to the suppressive effect of anti-retroviral drugs on physiological apoptosis, these therapies are associated with alteration of TNF-alpha-regulated T cell homeostasis, leading to an accumulation in the blood of T cells primed for TNF-alpha synthesis, and contributing to the development of a new syndrome associated with these treatments, the lipodystrophy syndrome.

Animals↗
PubMed2000

Down-regulated RPS3a/nbl expression during retinoid-induced differentiation of HL-60 cells: a close association with diminished susceptibility to actinomycin D-stimulated apoptosis.

The efficacy of anticancer agents significantly depends on the differential susceptibility of undifferentiated cancer cells and differentiated normal cells to undergo apoptosis. We previously found that enhanced expression of RPS3a/nbl, which apparently encodes a ribosomal protein, seems to prime cells for apoptosis, while suppressing such enhanced expression triggers cell death. The present study found that HL-60 cells induced to differentiate by all-trans retinoic acid did not undergo apoptosis following treatment with actinomycin D whereas undifferentiated HL-60 cells were highly apoptosis-susceptible, confirming earlier suggestions that differentiated cells have diminished apoptosis-susceptibility. Undifferentiated HL-60 cells highly expressed RPS3a/nbl whereas all-trans retinoic acid -induced differentiated cells exhibited markedly reduced levels, suggesting that apoptosis-resistance of differentiated cells could be due to low RPS3a/nbl expression. Down-regulation of enhanced RPS3a/nbl expression was also observed in cells induced to differentiate with the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1- propenyl]benzoic acid without any significant induction of cell death. While down-regulation of RPS3a/nbl expression during differentiation did not apparently induce apoptosis, RPS3a/nbl antisense oligomers triggered death of undifferentiated HL-60 cells, but not of retinoid-induced differentiated cells. It therefore seems that while down-regulation of enhanced RPS3a/nbl expression can induce apoptosis in undifferentiated cells, down-regulation of enhanced RPS3a/nbl expression during differentiation occurs independently of apoptosis, and could be regarded as reverting the primed condition to the unprimed (low RPS3a/nbl) state.

Antigens, Differentiation↗
PubMed1999

Enhanced survival and potent expansion of the natural killer cell population of HIV-infected individuals by exogenous interleukin-15.

The CD56+CD16+ natural killer (NK) cell population plays a crucial role in eliminating virus-infected cells and is diminished in HIV-infected individuals. This study examined the effects of exogenous interleukin (IL)-15 on proliferation and survival of CD56+ and CD16+ cells of HIV-infected individuals. When used at equivalent concentrations in vitro, IL-15 was more potent than IL-2 as a growth factor for CD56+ cells, as well as for CD16+ cells and also CD4+ and CD8+ T cells. Analysis of cell survival in etoposide-treated cultures indicated that IL-15 was also more potent than IL-2 as a survival factor for CD56+ cells by virtue of its greater ability to up-regulate bcl-2 expression. Although IL-15-induced proliferation of CD56+ cells was accompanied by increased apoptosis, IL-15 was more effective than IL-2 in increasing the representation of viable CD56+ cells in the peripheral blood mononuclear cell population, but less effective in increasing T cell representation. The immunotherapeutic potential of IL-15 appears superior to IL-2 in regard to expanding NK cell populations in HIV-infected individuals, but needs to be weighed against poorer increases in T cell populations.

Antigens, CD↗
PubMed1999

Interleukin-15 is a potent survival factor in the prevention of spontaneous but not CD95-induced apoptosis in CD4 and CD8 T lymphocytes of HIV-infected individuals. Correlation with its ability to increase BCL-2 expression.

IL-15 shares many biological properties with IL-2, a cytokine whose administration to HIV-infected individuals has been effective in enhancing depleted CD4 T lymphocyte numbers. The present study examined whether exogenous IL-15 could protect lymphocytes of HIV-infected individuals from spontaneous apoptosis, associated with growth factor deprivation, and CD95-induced apoptosis, which is believed to play a major role in T lymphocyte loss and HIV pathogenesis. Although IL-15, like IL-2, failed to inhibit CD95-induced lymphocyte apoptosis in vitro, IL-15 was found to act as a potent survival factor in the prevention of spontaneous apoptosis. The greater enhancement of lymphocyte survival, promoted by IL-15 as compared with IL-2 when used at an equivalent concentration, was associated with higher up-regulation of bcl-2 expression. In addition, IL-15 was more potent than IL-2 in stimulating lymphocyte proliferation. Despite the strong ability of IL-15 to promote both lymphocyte survival and proliferation, the increases in representation and total numbers of viable cells induced by IL-15 were not higher than those induced by IL-2. This appears to be associated with the greater ability of IL-15 to activate lymphocytes and increase their apoptosis-susceptibility. Therefore, lymphocyte loss occurring by growth factor deprivation in HIV infection may be potentially prevented by IL-15, although its benefits for survival need to be closely assessed against its ability to augment lymphocyte activation.

Apoptosis↗
PubMed1999

Activation, survival and apoptosis of CD45RO+ and CD45RO- T cells of human immunodeficiency virus-infected individuals: effects of interleukin-15 and comparison with interleukin-2.

HIV infection is associated with increased representation of T cells bearing an activated, memory (CD45RO+) phenotype. Although administration of antiretroviral agents and interleukin-2 (IL-2) augment depleted CD4+ T-cell numbers, such therapies have been preferentially beneficial for CD45RO+ T cells. Interleukin-15 (IL-15) exhibits many biological activities in common with IL-2, including promoting T-cell survival and proliferation. The present study found that these two cytokines differed in their ability to induce proliferation, enhance survival, and control apoptosis of CD45RO+ and CD45RO- T-cell populations of human immunodeficiency- (HIV) infected individuals. When used at equivalent concentrations in vitro, IL-15 was more potent than IL-2 in activating and stimulating proliferation of CD4+CD45RO+, CD8+CD45RO+ and CD8+CD45RO- cells, but failed to be more effective than IL-2 in reducing apoptosis. Poor activation of CD4+CD45RO- cells by IL-15 and to IL-2 appeared to be attributable to low expression of the beta receptor chain utilized by both cytokines. However, IL-15 was more effective than IL-2 in enhancing survival of the CD4+CD45RO- population, suggesting a greater protective effect of IL-15 for naive CD4+ T cells, which are preferentially lost in HIV-infected individuals.

Apoptosis↗
PubMed1999

Involvement of ribosomal proteins in regulating cell growth and apoptosis: translational modulation or recruitment for extraribosomal activity?

Gene recruitment is a mechanism of molecular evolution whereby a gene product can function in more than one distinct capacity. The 'one gene-dual function' phenomenon is well illustrated by crystallins, structural proteins that play both specialized roles in the eye lens and also 'housekeeping' enzyme roles. Ribosomal proteins are integral components of the basal cellular machinery involved in protein synthesis, whose roles have been regarded collectively as important, but individually somewhat mundane. However, various individual ribosomal proteins and also translation initiation and elongation factors have been found to play roles in regulating cell growth, transformation and death, giving rise to increasing speculation that components of the translational apparatus can act as multifunctional proteins. Recently, we have shown that ribosomal protein S3a (RPS3a) plays important roles in cell transformation and death, whereby constitutively or transiently enhanced RPS3a expression can be regarded as 'priming' a cell for apoptosis and suppression of such enhanced expression as 'execution'. While it is unclear whether RPS3a acts in a capacity mechanistically distinct from that in translation, such a possibility is discussed in this article in the light of recent, although not exhaustively reviewed, findings implicating the involvement of other individual ribosomal proteins in modulating and/or effecting changes in cellular responses and growth patterns in an extraribosomal capacity independent of their conventional role in translation.

Animals↗
PubMed1998

Altered cellular responses by varying expression of a ribosomal protein gene: sequential coordination of enhancement and suppression of ribosomal protein S3a gene expression induces apoptosis.

A growing body of evidence indicates that individual ribosomal proteins and changes in their expression, participate in, and modulate, a variety of cellular activities. Our earlier studies have found that apoptosis could be induced by inhibiting expression of ribosomal protein S3a (RPS3a) in many tumor cells which constitutively express RPS3a at levels much higher than in normal cells. This study aimed to investigate cellular responses to enhancement of RPS3a expression, and whether apoptosis could be induced by sequential alterations in RPS3a expression involving enhancement from an initially low constitutive level, followed by suppression. Stably transfected NIH 3T3- derived cell lines were established in which exogenous RPS3a expression could be readily manipulated. Enhancement of RPS3a expression appeared to induce transformation as assessed by well-established criteria such as foci formation and anchorage-independent growth in vitro, and formation of tumors in nude mice. These properties were compared with those observed in ras-transformed NIH 3T3 cells. Apparent transformation occurred only when enhanced RPS3a-expressing cells were in close cell-cell contact. Suppression of enhanced RPS3a expression was observed to induce apoptosis as assessed by various morphological and biochemical characteristics including cell shrinkage, membrane blebbing, chromatin condensation, nuclear and cell fragmentation, phosphatidylserine externalization, and internucleosomal DNA fragmentation. This induction of apoptosis was not specific to apparently transformed cells, as cells at low confluence, which likewise expressed RPS3a at enhanced levels but exhibited no morphological transformation, underwent apoptosis when RPS3a expression was inhibited. These results support a role for RPS3a in the apoptotic process, but not as an oncoprotein per se.

3T3 Cells↗
PubMed1998

Multinucleation and preservation of nucleolar integrity of macrophages.

Rat bone marrow-derived macrophages formed multinucleated giant cells spontaneously when cultured in slide glass chambers or when induced with the polyanion acetyl lignin. Nuclei in such cells tended to cluster in distinct rings. DNA fragmentation appeared to occur in multinucleated cells, as detected by 3' end-labeling. Southern blot analyses, using probes specific for nucleolar and non-nucleolar genes, indicated that chromatin DNA was fragmented whereas nucleolar DNA was relatively intact. Autoradiography revealed preservation, in multinucleated cells, of nucleoli into which radiolabeled uridine was incorporated. Multinucleated macrophages appeared to eventually fragment. Preserved integrity of nucleoli seems to be a feature of macrophage multinucleation, a process which apparently culminates in cell death.

Animals↗
PubMed1998

Antisense sequences of the nbl gene induce apoptosis in the human promyelocytic leukemia cell line HL-60.

Apoptosis is induced by the transcriptional inhibitor actinomycin D (Act D) in various cell types, particularly many leukemic cell lines such as HL-60. A common feature of these cell lines is their high constitutive expression level of the nbl gene, which was originally isolated by virtue of its abundance in a Namalwa Burkitt lymphoma cDNA library. In contrast, cell lines which constitutively express nbl at low levels appear not to undergo typical apoptotic death in response to Act D. Apoptotic induction by Act D in cells which normally express nbl at high levels was found in this study to be closely associated with a decline in nbl mRNA levels, raising the possibility that apoptosis could be induced by lowering nbl expression levels in such cells. Transient expression of nbl antisense sequences in HL-60 cells decreased cell viability, and induced typical apoptotic morphology such as cell shrinkage, chromatin condensation and nuclear fragmentation. Incubation with nbl antisense oligomers also induced similar features in HL-60 cells and in another high nb-expressing cell line, Jurkat, but had little effect in HepG2 cells which constitutively express nbl at low levels. These findings suggest that lowering constitutively high levels of nbl expression can induce apoptosis.

Antineoplastic Agents, Hormonal↗
PubMed1998

Regulation of tumor growth as a 'total mass' in mice: apoptosis as a major mechanism in altering growth rates of single and multiple coexisting tumor nodules.

Earlier studies have suggested that a solid tumor behaves, in its general pattern of growth, like a normal integrated organ. In this study, the growth patterns of spherically shaped tumor nodules are re-examined using an accurate tumor volume-measuring procedure, with the aim of investigating the possible role of apoptosis in regulating tumor growth. Observations revealed at least three distinct phases of growth: rapid growth phase I, slower growth phase II and 'stationary' phase III. Transition from one phase to the next was primarily due to an increase in the level of apoptosis and not to a decrease in the cell proliferation rate. The level of apoptosis, at a given phase, was similar in a single nodule and each of the multiple coexisting nodules of the same tumor line. However, temporal shifts in apoptosis levels caused early phase transition in coexisting nodules, such that their total volume was the same as that of a single nodule. It can be concluded that apoptosis appears to be a primary mechanism regulating tumor growth as a 'total mass', irrespective of whether the tumor exists in one or multiple nodules, if derived from the same tumor line.

3T3 Cells↗
PubMed1997

Deuterium oxide (heavy water) accelerates actin assembly in vitro and changes microfilament distribution in cultured cells.

While deuterium oxide (D2O) is known to produce various biological effects in living animals and cultured cells, the detailed mechanisms by which it does so remain unclear. The present study was designed to assess the effects of D2O on microfilaments (MFs) via fluorescence staining of BALB 3T3 cells and in vitro actin polymerization studies. After BALB 3T3 cells had been exposed to a concentration of more than 30% D2O for several hours, stress fibers in the peripheral region became thick and distinct, while the quantity of perinuclear MFs was drastically reduced. This effect was transient and returned to the original distribution within 12 h. Cytoplasmic F-actin (FA) also increased transiently coincident with the enhancement of stress fibers. The pattern of cell locomotion became simpler, and total locomotor activity was suppressed in a D2O concentration-dependent manner. Analysis of in vitro studies demonstrated that, when purified G-actin was polymerized in D2O at a concentration greater than 10%, the rate of actin polymerization was accelerated, whereas the total amount of polymerized actin at the steady state in D2O was the same as that in H2O controls. A gelation assay and transmission electron microscopy (TEM) showed that the network of crosslinked FA with alpha-actinin became denser in 30% D2O than in H2O. These findings concerning actin polymerization and FA gelation suggest that the alteration of stress fibers in cultured cells is caused by a direct effect of D2O on cellular MF dynamics.

3T3 Cells↗
PubMed1996

Constitutively enhanced nbl expression is associated with the induction of internucleosomal DNA cleavage by actinomycin D.

Previous studies have found nbl expression to transiently rise and fall during glucocorticoid-induced thymic apoptosis. This induction of apoptosis is blocked by the transcriptional inhibitor actinomycin D. However, actinomycin D can trigger apoptosis in other cell types, e.g., HL-60 cells. This study found that internucleosomal DNA cleavage typical of apoptosis is induced by actinomycin D in cell lines such as HL-60 which constitutively express high levels of nbl above a certain "threshold." In contrast, "DNA ladder" formation was not induced by actinomycin D in cell lines with low constitutive nbl expression. Enhanced nbl expression therefore appears to be associated with apoptosis which is either blocked or induced by actinomycin D.

Amnion↗