Biomedical subjects

X Zhao

Publications and source records attributed to X Zhao.

At least 433 records · Page 24Linked to original sources

PubMed1997

Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21(waf1/cip1) and p27(kip1) and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells.

The molecular mechanisms underlying protein kinase C (PKC) isozyme-mediated control of cell growth and cell cycle progression are poorly understood. Our previous analysis of PKC isozyme regulation in the intestinal epithelium in situ revealed that multiple members of the PKC family undergo changes in expression and subcellular distribution precisely as the cells cease proliferating in the mid-crypt region, suggesting that activation of one or more of these molecules is involved in negative regulation of cell growth in this system (Saxon, M. L., Zhao, X., and Black, J. D. (1994) J. Cell Biol. 126, 747-763). In the present study, the role of PKC isozyme(s) in control of intestinal epithelial cell growth and cell cycle progression was examined directly using the IEC-18 immature crypt cell line as a model system. Treatment of IEC-18 cells with PKC agonists resulted in translocation of PKC alpha, delta, and epsilon from the soluble to the particulate subcellular fraction, cell cycle arrest in G1 phase, and delayed transit through S and/or G2/M phases. PKC-mediated cell cycle arrest in G1 was accompanied by accumulation of the hypophosphorylated, growth-suppressive form of the retinoblastoma protein and induction of the cyclin-dependent kinase inhibitors p21(waf1/cip1) and p27(kip1). Reversal of these cell cycle regulatory effects was coincident with activator-induced down-regulation of PKC alpha, delta, and epsilon. Differential down-regulation of individual PKC isozymes revealed that PKC alpha in particular is sufficient to mediate cell cycle arrest by PKC agonists in this system. Taken together, the data implicate PKC alpha in negative regulation of intestinal epithelial cell growth both in vitro and in situ via pathways which involve modulation of Cip/Kip family cyclin-dependent kinase inhibitors and the retinoblastoma growth suppressor protein.

Animals↗

PubMed1997

Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway.

Epithelial cells are dependent upon adhesion to extracellular matrix for survival. We show that loss of beta1 integrin receptor contact with extracellular matrix signals the inhibition of G1 cyclin-dependent kinase activity. This loss of cyclin-dependent kinase activity leads to accumulation of the hypophosphorylated (active) form of the retinoblastoma tumor suppressor protein (Rb). We present evidence that in epithelial cells deprived of matrix contact, the growth suppression signal elicited by hypophosphorylated Rb opposes stimulatory signals from serum growth factors, leading to a cell cycle conflict that triggers apoptosis. This apoptotic pathway is modulated by Bcl-2 through a novel mechanism that regulates Rb phosphorylation. We present evidence that the Rb-dependent apoptotic pathway functions in vivo in the apoptosis of the prostate glandular epithelium following castration.

Animals↗

PubMed1997

Structural analysis of membrane-bound retrovirus capsid proteins.

We have developed a system for analysis of histidine-tagged (His-tagged) retrovirus core (Gag) proteins, assembled in vitro on lipid monolayers consisting of egg phosphatidylcholine (PC) plus the novel lipid DHGN. DHGN was shown to chelate nickel by atomic absorption spectrometry, and DHGN-containing monolayers specifically bound gold conjugates of His-tagged proteins. Using PC + DHGN monolayers, we examined membrane-bound arrays of an N-terminal His-tagged Moloney murine leukemia virus (M-MuLV) capsid (CA) protein, His-MoCA, and in vivo studies suggest that in vitro-derived His-MoCA arrays reflect some of the Gag protein interactions which occur in assembling virus particles. The His-MoCA proteins formed extensive two-dimensional (2D) protein crystals, with reflections out to 9.5 A resolution. The image-analyzed 2D projection of His-MoCA arrays revealed a distinct cage-like network. The asymmetry of the individual building blocks of the network led to the formation of two types of hexamer rings, surrounding protein-free cage holes. These results predict that Gag hexamers constitute a retrovirus core substructure, and that cage hole sizes define an exclusion limit for entry of retrovirus envelope proteins, or other plasma membrane proteins, into virus particles. We believe that the 2D crystallization method will permit the detailed analysis of retroviral Gag proteins and other His-tagged proteins.

Amino Acid Sequence↗

PubMed1997

The role of cysteine residues in the rearrangement of uridine to pseudouridine catalyzed by pseudouridine synthase I.

Escherichia coli tRNA pseudouridine synthase I (PSUI) catalyzes the conversion of uridine residues to pseudouridine in positions 38, 39, and 40 of various tRNA molecules. In previous biochemical studies with this enzyme (Kammen, H. O., Marvel, C. C., Hardy, L., and Penhoet, E. E. (1988) J. Biol. Chem. 263, 2255-2263) it was reported that cysteine residues are important in maintaining the active structure of the enzyme and are possibly involved in the catalytic reaction mechanism via a covalent cysteine intermediate. In order to further investigate the biochemical properties of PSUI, a high level expression and purification system for the enzyme and its corresponding mutants was developed. PSUI has three cysteine residues among 270 amino acids. In the present investigation, each cysteine residue was individually changed to serine and alanine. In addition, a triple mutant was prepared wherein all three cysteine residues were replaced by alanine. Surprisingly, while two of the three cysteine to serine mutants were inactive, all alanine mutants exhibited near wild-type levels of activity, including the triple mutant. These results provide the first direct and unambiguous chemical evidence against a covalent cysteine intermediate in the rearrangement mechanism of uridine to pseudouridine.

Catalysis↗

PubMed1997

The ototoxicity of trichloroethylene: extrapolation and relevance of high-concentration, short-duration animal exposure data.

Inhalation exposure to high concentrations of 1,1, 2-trichloroethylene (TCE) has been shown to damage hearing in the mid-frequency range in the rat. The present study directly evaluated the adequacy of high-concentration, short-term exposures to TCE for predicting the neurotoxicity produced by longer duration exposures. Adult male Long-Evans rats (n = 10-12 per group) were exposed to TCE via inhalation (whole body) in 1-m3 stainless steel flow-through chambers for 6 hr/day, 5 days/week. The following exposures were used: 1 day (4000-8000 ppm), 1 week (1000-4000 ppm), 4 weeks (800-3200 ppm), and 13 weeks (800-3200 ppm). Air-only exposed animals served as controls. Auditory thresholds were determined for a 16-kHz tone 3-5 weeks after exposure using reflex modification audiometry. Results replicated previous findings of a hearing loss at 16 kHz for all exposure durations. The dB15 concentrations (concentration that increases thresholds by 15 dB) for 16-kHz thresholds were 6218, 2992, 2592, and 2160 ppm for the 1-day, 1-week, 4-week and 13-week exposures, respectively. These data demonstrate that the ototoxicity of TCE was less than that predicted by a strict concentration x time relationship. These data also demonstrate that simple models of extrapolation (i.e., C x t = k, Haber's Law) overestimate the potency of TCE when extrapolating from short-duration to longer-duration exposures. Furthermore, these data suggest that, relative to ambient or occupational exposures, the ototoxicity of TCE in the rat is a high-concentration effect.

Administration, Inhalation↗

PubMed1997

A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat.

The capacity of a calpain inhibitor to reduce losses of neurofilament 200-, neurofilament 68- and calpain 1-mediated spectrin breakdown products was examined following traumatic brain injury in the rat. Twenty-four hours after unilateral cortical impact injury, western blot analyses detected neurofilament 200 losses of 65% (ipsilateral) and 36% (contralateral) of levels observed in naive, uninjured rat cortices. Neurofilament 68 protein levels decreased only in the ipsilateral cortex by 35% relative to naive protein levels. Calpain inhibitor 2, administered 10 min after injury via continuous arterial infusion into the right external carotid artery for 24 h, significantly reduced neurofilament 200 losses to 17% and 3% relative to naive neurofilament 200 protein levels in the ipsilateral and contralateral cortices, respectively. Calpain inhibitor administration abolished neurofilament 68 loss in the ipsilateral cortex and was accompanied by a reduction of putative calpain-mediated neurofilament 68 breakdown products. Spectrin breakdown products mediated by calpain 1 activation were detectable in both hemispheres 24 h after traumatic brain injury and were substantially reduced in animals treated with calpain inhibitor 2 both ipsilaterally and contralaterally to the site of injury. Qualitative immunofluorescence studies of neurofilament 200 and neurofilament 68 confirmed western blot data, demonstrating morphological protection of neuronal structure throughout cortical regions of the traumatically injured brain. Morphological protection included preservation of dendritic structure and reduction of axonal retraction balls. In addition, histopathological studies employing hematoxylin and eosin staining indicated reduced extent of contusion at the injury site. These data indicate that calpain inhibitors could represent a viable strategy for preserving the cytoskeletal structure of injured neurons after experimental traumatic brain injury in vivo.

Animals↗

PubMed1997

Effects of calcium antagonist felodipine on renal sympathetic nerve activity in rats with congestive heart failure.

In order to assess the effects of dihydropyridine calcium antagonist on sympathetic nerve activity (SNA) in experimental chronic heart failure (CHF), felodipine was given to rats with CHF induced by coronary artery ligation. Anesthetized CHF (n = 7) and sham-operated (n = 9) rats were injected with a bolus dose of felodipine (20 microg/kg) and then infused with felodipine (30 microg/kg/h) for 3 hours. Control CHF rats (n = 8) were given vehicle in the same way. After felodipine treatment, mean blood pressure (MBP) rapidly decreased to 75-85 mmHg, and there was a reflex tachycardia and reflex activation of renal SNA. The heart rate (HR) had returned to baseline level after 3 hours of continuous felodipine infusion, and the SNA returned to baseline level after 2 hours of infusion. At the end of the experiment, renal SNA was 65.4 +/- 11.5% of the baseline level in CHF rats receiving felodipine (P < 0.05) and 94.1 +/- 22.8% in CHF rats receiving vehicle (P > 0.05), but there was no statistical difference between the two groups. Arterial baroreceptor sensitivity (assessed by phenylephrine infusion), which was impaired in CHF rats (-2.7 +/- 0.2 SNA%/mmHg in all CHF rats together vs. -3.6 +/- 0.4 in sham-operated rats, P < 0.5) did not differ significantly from that in sham-operated rats during felodipine infusion (-3.2 +/- 0.4 in felodipine-treated CHF rats vs. -3.7 +/- 0.6 in sham-operated rats) but deteriorated without felodipine treatment (-2.1 +/- 0.3 in CHF rats receiving vehicle, P < 0.05). The biphasic renal SNA response during felodipine infusion suggests that felodipine does not cause persistent sympathetic activation and relatively improves baroreceptor sensitivity in CHF rats.

Animals↗

PubMed1997

High efficiency DNA delivery into swine oocytes and embryos by electronic pulse delivery (EPD).

The production of transgenic swine for xenotransplantation has been proposed as an optimal option to overcome the chronic shortage of human organ donors. Generation of genetically engineered swine has been elusive due to the difficulties in gene transfer. In order to achieve effective gene delivery, a key step for the genetic modification, we applied electronic pulse delivery (EPD) technology to introduce H2Kb-DC DNA construct into swine eggs. Using the developed EPD Protocols, we have achieved good viability of the EPD treated oocytes, satisfactory embryonic development of the EPD treated embryos, and stable DNA transfer into the swine embryos with high efficiency. Thus, application of the EPD technology promises to effectively facilitate the generation of large transgenic mammals.

Animals↗

PubMed1997

Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy.

Glomerular rigidity limits the glomerular expansion and mesangial cell (MC) stretch induced by variations in intracapillary pressure. In tissue culture, MC stretch stimulates synthesis of extracellular matrix components (ECM). Therefore, altered glomerular rigidity in diabetes may influence ECM accumulation by modulating the glomerular distention and MC stretch associated with glomerular hypertension. An ambient of high glucose concentration per se also enhances MC formation of ECM, possibly altering the cellular response to mechanical stretch. In this study, compliance was measured in isolated perfused glomeruli from streptozotocin-injected rats at four days (4d-D), five weeks (5w-D) and six months (6m-D) after induction of diabetes. In addition, collagen metabolism induced by stretch was investigated in MC cultured in 8 and 35 mM glucose concentrations. Glomerular compliance was normal in 5w-D rats and moderately increased in 4d-D (16%) and 6m-D animals (14%). As compared to static cultures. MC stretch increased total collagen synthesis (8 mM, 50%; 35 mM, 27%) and catabolism. However, while the fraction of newly formed collagen being catabolized increased in 8 mM-stretched cultures, in 35 mM-stretched it was unchanged. This resulted in marked increase in the net collagen accumulated in the incubation medium (4 vs. 24%) and cell layer 5 vs. 15%) only in the latter. In diabetes, the largely unaltered glomerular stiffness renders hypertension-induced MC stretch unopposed. More importantly, the accumulation of ECM caused by any degree of mechanical strain is greatly aggravated in a milieu of high glucose concentration.

Animals↗

PubMed1997

Effects of hydralazine on renal sympathetic nerve activity in normal and congestive heart failure rats.

We investigated the effects of hydralazine on renal sympathetic nerve activity in anaesthetized heart failure rats. Sham-operated rats (group 1) received 0.5 mg kg-1 of hydralazine as bolus and were then infused with 0.3-0.5 mg kg-1 h-1 for 3 h intravenously. Heart failure rats received either the same regime (group 2) as group 1, or the same volume of vehicle (group 3). Heart failure rats exhibited lower mean blood pressure (P < 0.05) and elevated renal sympathetic nerve activity (P < 0.01) in the basal state. In group 2, the mean blood pressure decreased 26% after 30 min of hydralazine administration and remained lower for 3 h, with unchanged renal sympathetic nerve activity. In group 1, the mean blood pressure decreased 36%, and the heart rate and renal sympathetic nerve activity were significantly inhibited. Bilateral vagotomy did not alter renal sympathetic nerve response to hydralazine, but resulted in tachycardia. The results indicate that hydralazine, despite its profound hypotensive effect, did not activate renal sympathetic nerve activity in heart failure rats and inhibited renal sympathetic nerve activity in sham-operated rats. This inhibition was not mediated through the vagal nerve.

Animals↗

PubMed1997

Mechanisms of calpain proteolysis following traumatic brain injury: implications for pathology and therapy: implications for pathology and therapy: a review and update.

Much recent research has focused on the pathological significance of calcium accumulation in the central nervous system (CNS) following cerebral ischemia, spinal cord injury (SCI), and traumatic brain injury (TBI). Disturbances in neuronal calcium homeostasis may result in the activation of several calcium-sensitive enzymes, including lipases, kinases, phosphatases, and proteases. One potential pathogenic event in a number of acute CNS insults, including TBI, is the activation of the calpains, calcium-activated intracellular proteases. This article reviews new evidence indicating that overactivation of calpains plays a major role in the neurodegenerative cascade following TBI in vivo. Further, this article presents an overview from in vivo and in vitro models of CNS injuries suggesting that administration of calpain inhibitors during the initial 24-h period following injury can attenuate injury-induced derangements of neuronal structure and function. Lastly, this review addresses the potential contribution of other proteases to neuronal damage following TBI.

Animals↗

PubMed1997

Immunohistochemical study of calpain-mediated breakdown products to alpha-spectrin following controlled cortical impact injury in the rat.

This study examined the effect of unilateral controlled cortical impact on the appearance of calpain-mediated alpha-spectrin breakdown products (BDPs) in the rat cortex and hippocampus at various times following injury. Coronal sections were taken from animals at 15 min, 1 h, 3 h, 6 h, and 24 h after injury and immunolabeled with an antibody that recognizes calpain-mediated BDPs to alpha-spectrin (Roberts-Lewis et al., 1994). Sections from a separate group of rats were also taken at the same times and stained with hematoxylin and eosin. Analyses of early time points (15 min, 1 h, 3 h, and 6 h following injury) revealed alpha-spectrin BDPs in structurally intact neuronal soma and dendrites in cortex ipsilateral to site of injury that was not present in tissue from sham-injured control rats. By 24 h after injury labeling was not restricted to clearly defined neuronal structures in ipsilateral cortex, although there was an increased extent of diffuse labeling. BDPs to alpha-spectrin in axons were not detected until 24 h after injury, in contrast to the more rapid accumulation of BDPs observed in neuronal soma and dendrites. The presence of BDPs to alpha-spectrin in the cortex at the site of impact, and in the rostral and contralateral cortex, coincided with morphopathology detected by hematoxylin and eosin. alpha-Spectrin BDPs were also observed in the hippocampus ipsilateral to the injury in the absence of overt cell death. This investigation provides further evidence that calpain is activated after controlled cortical impact and could contribute to necrosis at the site of injury. The appearance of calpain-mediated BDPs at sites distal to the contusion site and in the hippocampus also suggests that calpain activation may precede and/or occur in the absence of extensive morphopathological changes.

Animals↗

PubMed1997

DNA gyrase, topoisomerase IV, and the 4-quinolones.

For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.

Bacteria↗

PubMed1997

Molecular evidence for a vascular smooth muscle H+-K+-ATPase.

Evidence for an H+-K+-adenosinetriphosphatase (HKA) in vascular smooth muscle cells has recently been demonstrated in the rat aorta and a rat smooth muscle cell line (A(7)r(5)) by functional studies. Our laboratory has used reverse transcriptase (RT)-polymerase chain reaction (PCR) and Northern hybridization techniques to define the type of HKA present in canine whole carotid artery and confluent carotid artery cells. PCR primers to detect an HKA message of unknown isoform were designed on the basis of homology to known sequences of gastric, colonic, and toad bladder HKA isoforms and dissimilarity to the Na+-K+-adenosinetriphosphatase isoforms. A PCR product of predicted size was generated from cDNAs of both confluent cells and whole vessel carotid artery that possess 91% nucleotide sequence identity to the canine gastric HKA. Northern hybridization with the PCR product as a probe revealed hybridization to whole vessel carotid artery, cultured confluent carotid artery cell, kidney, and stomach canine total RNA at the known message size for the gastric HKA isoform. These data suggest that vascular smooth muscle cells express an HKA mRNA that may be identical to the gastric isoform.

Amino Acid Sequence↗

PubMed1997

cAMP and purinergic P2y receptors upregulate and enhance inducible NO synthase mRNA and protein in vivo.

Adenosine 3',5'-cyclic monophosphate (cAMP) and purinergic P2y receptor agonists upregulate inducible nitric oxide (NO) synthase (iNOS) but inhibit Escherichia coli endotoxin lipopolysaccharide (LPS)- and cytokine-mediated upregulation of iNOS in cultured cells. We examined the effects of cAMP and P2y receptor agonists on the iNOS system in vivo. Intratracheal administration of dibutyryl-cAMP (DBcAMP, 0.1 and 1 mg/kg), a P2y receptor agonist [2-methylthioadenosine 5'-triphosphate (MeS-ATP), 5 mg/kg], or LPS (0.6 mg/kg) to rats 2 h before bronchoalveolar lavage (BAL) increased iNOS mRNA (competitor-equalized reverse transcription-polymerase chain reaction) and iNOS protein (Western blot) in rat alveolar macrophages compared with the effects of sterile phosphate-buffered saline (0.5 ml it). At equal levels of upregulation of iNOS mRNA, 1) LPS, but not DBcAMP or MeS-ATP, upregulated nuclear transcription factor-kappa B (NF-kappa B) and 2) iNOS protein and formation of NO were greater in alveolar macrophages from LPS- and MeS-ATP-treated rats than from DBcAMP-treated rats. Administration of DBcAMP or MeS-AMP 15 min before LPS did not inhibit LPS-induced alveolar macrophage-derived iNOS mRNA, iNOS protein, and NO. Diethyldithiocarbamate (DETC, 5 mg/kg it) inhibited LPS-induced iNOS mRNA but did not affect upregulation of iNOS mRNA produced by the other agonists. We conclude that an LPS-dependent and -independent pathway of iNOS mRNA induction exists in vivo. The former is activated by IPS and most cytokines, is associated with upregulation of NF-kappa B and inhibited by DETC, and elicits an inflammatory response. The latter, activated by DBcAMP and MeS-ATP, is not associated with upregulation of NF-kappa B, inhibition by DETC, or activation of inflammation. The two systems are additive in vivo rather than antagonistic. Speculatively, if the LPS-independent iNOS pathway exists in humans, the iNOS in tissues from patients taking drugs affecting cAMP or P2y receptors may be iatrogenic rather than pathogenetic in origin.

Adenosine Triphosphate↗

PubMed1997

Effects of NO synthase inhibitors, arginine-deficient diet, and amiloride in pregnant rats.

This study tests the hypothesis that nitric oxide synthase (NOS) inhibition is linked to NG-nitro-L-arginine methyl ester (L-NAME)-mediated intrauterine growth retardation (IUGR) and fetal limb reduction deficits (LRD) in pregnant dams. Administration of L-NAME (1 mg/ml) or aminoguanidine (AG, 500 micrograms/ml) in the drinking water or intraperitoneal administration of L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 mg.kg-1.day-1) on gestational days 13-20 decreased nitrite and nitrate plus nitrate (RNI) levels in the urine and plasma and decreased RNI in incubates of aorta and fetal limbs compared with pregnant rats given amiloride (50 micrograms/ml) or water (control). Although all drugs caused fetal IUGR, only L-NAME and amiloride caused fetal deaths and LRD. Urine and tissue levels of RNI were unchanged in rats fed and arginine-free diet (AFD) on gestational days 13-20, and yet fetal IUGR, deaths, and LRD were prevalent. L-NAME potentiated the fetal abnormalities and resorptions. Plasma arginine concentrations decreased with AFD > > L-NAME > L-NIO. Plasma ornithine, a precursor for polyamine synthesis, decreased with AFD and increased with L-NAME. Thus inhibition of NOS is not linked to LRD. The ability of L-NAME and amiloride to produce fetal IUGR and LRD may result from L-NAME-mediated modulation of amino acid delivery to the fetus and amiloride-mediated inhibition of protein synthesis. Finally, IUGR appears unrelated to LRD.

Abnormalities, Drug-Induced↗

PubMed1997

Bioavailability of vitamin E compounds and the effect of supplementation on release of superoxide and hydrogen peroxide by bovine neutrophils.

The effects of daily supplementation of 1000 IU of d-alpha- or dl-alpha-tocopherol acetate to Holstein cows from drying off to 8 wk after calving were studied 1) to compare the bioavailability of d-alpha- and dl-alpha-tocopherol acetate by monitoring vitamin E concentrations in plasma, red blood cells, and neutrophils and 2) to determine the effect of d-alpha- and dl-alpha-tocopherol acetate supplementation on O2- and H2O2 release by neutrophils. Supplementation with d-alpha- or dl-alpha-tocopherol acetate increased vitamin E concentrations in blood plasma, red blood cells, and neutrophils; the d-alpha form was more effective than was the dl-alpha form. Supplementation with d-alpha- or dl-alpha-tocopherol acetate had no effect on the release of O2- and H2O2 by neutrophils, suggesting no harmful effects on surrounding tissues from oxygen-free radicals produced by neutrophils.

Animals↗

PubMed1997

[Apoptosis and expression of its regulating genes in adenoma and adenocarcinoma of large intestine].

OBJECTIVE: To investigate the effects of apoptosis and its regulating genes in different stages of malignant transformation of large intestine epithelium in colorectal adenoma and adenocarcinoma. METHODS: The density and distribution of the apoptotic cells and the positive expression of p53 and bcl-2 oncoprotein were observed in situ in 32 villous adenomas and 33 papillary adenocarcinomas of the large intestine, using DNA nick end labelling technique and immunohistochemical staining for p53 and bcl-2 oncoprotein. 15 nontumor mucosa were used as controls. RESULTS: The density of apoptotic cells in adenoma and adenocarcinoma was significantly higher than that in nontumor mucosa (P < 0.01), and their density in adenoma was higher than in adenocarcinoma (P < 0.01). The positive rate and staining intensity of p53 and bcl-2 oncoprotein in adenoma and adenocarcinoma were significantly higher than in non tumor mucosa (P < 0.01), their staining intensity in adenocarcinoma was higher than that in adenoma (P < 0.01). In adenoma, the density of apoptotic cells in the bcl-2 oncoprotein positive group was higher than that in the bcl-2 oncoprotein negative group (P < 0.01). CONCLUSION: The abnormal regulation of apoptosis may play an important role in the pathogenesis of large intestine carcinoma. The bcl-2 oncoprotein can inhibit apoptosis in adenoma and adenocarcinoma. However, mutational p53 oncoprotein may likely block apoptosis in adenocarcinoma.

Adenocarcinoma, Papillary↗