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PubMed2003

[Chronic tropical pancreatitis: a case report].

The purpose of this report is to describe a case of tropical calcific pancreatitis (TCP). This disease is specific to tropical regions and constitutes the main cause of chronic pancreatitis in children worldwide. It can also be observed in young adults (2nd and 3rd decade). Shortage of dietary lipids during childhood has been implicated in the development of TCP and mutation of the SPINK1 gene has been cited as a predisposing genetic factor. The underlying pathophysiology of TCP is the same as chronic calcific pancreatitis (CCP) due to alcohol abuse. The main features are a sex ratio of 1, absence of alcohol consumption, occurrence of childhood diabetes in one third of cases, low incidence of acidoketosis, and presence of macro-calcifications especially in ducts. In 10% of cases TCP is complicated by pancreatic carcinoma occurring at an early age, located mainly in the body and tail of the pancreas, and having a less favorable prognosis than primary cancer. Treatment of patients with TCP is the same as for patients with CCP due to alcohol abuse. Prevention depends on improvement of nutritional status of the population.

Adult↗

PubMed2004

Bone ingrowth into two porous ceramics with different pore sizes: an experimental study.

Many properties of porous calcium phosphate ceramics have been described, but how pore size influences bony integration of various porous ceramics remains unclear. This study was performed to quantify the bony ingrowth and biodegradability of two porous calcium phosphate ceramics with four different pore size ranges (45-80 microm, 80-140 microm, 140-200 microm, and 200-250 microm). Hydroxyapatite (HA) and beta-tricalcium phosphate (TCP) cylinders were implanted into the femoral condyles of rabbits and were left in situ for up to 12 months. The percentage of bone ingrowth and the depth of ingrowth within the pores were determined. Biodegradability of the implants was also evaluated. Bone ingrowth occurred at a higher rate into the TCP than into the HA ceramics with the same pore size ranges. The amount of newly formed bone was statistically smaller (p < 0.05) into ceramics with 45-80 microm pore size than with larger pore size, whatever the implantation time for HA and until four months for TCP. No statistical difference was noted between the three highest pore size ranges. No implant degradation was noted up to four months. Our results suggest that a pore size above 80 microm improves bony ingrowth in both HA and TCP ceramics. Bone formation was higher in the TCP than in the HA implants.

Animals↗

PubMed2005

[In vitro biocompatibility of novel absorbable hydroxyapatite and AO artificial bone beta-tricalcium phosphate with rhesus bone marrow stromal cells].

OBJECTIVE: To study the in vitro biocompatibility of novel hydroxyapatite (HA) and AO artificial bone beta-tricalcium phosphate (beta-TCP) with rhesus bone marrow stromal cells (rBMSCs) . METHODS: The third passage of rBMSCs were cultured with HA and beta-TCP respectively, with the cells cultured without the materials as the control. The morphology and proliferation of cells were observed by inverted phase-contrast microscope and scanning electron microscope (SEM). MTT assay was used to semiquantitatively evaluate the cell proliferation. RESULTS: The rBMSC cocultured with HA exhibited good growth as observed under inverted phase-contrast microscope, without significant difference from the cells in the control group. Some small particles were seen pealing off from beta-TCP, and some of the cells died. Under SEM, rBMSCs showed good adhesion to HA with obvious proliferation, but the ratio of adhesive cells was not as high as that in beta-TCP group. MTT assay showed no significant difference in the cell number between HA and the control groups, but the cell number in beta-TCP group was notably less than that of control group. CONCLUSION: Novel HA has good biocompatibility with rBMSCs for bone tissue engineering, and AO artificial bone still needs improvement to serve as scaffold material for BMSCs.

Absorbable Implants↗

PubMed2005

[Ectopic osteogenic ability of BMSCs on various scaffold materials in nude mice].

PURPOSE: To explore the ectopic osteogenic abilities of bone marrow stromal cells (BMSCs) on different scaffold materials in nude mice. METHODS: Canine BMSCs in vitro cultured were seeded at the density of 1x10(6)cells/cm(2) onto scaffolds of freeze-dried demineralized bone matrix (fdDBM), tricalcium phosphate (TCP), 200microm coralline hydroxyapatite (CH200) and 500microm coralline hydroxyapatite (CH500). The cell adherence and growth on the materials were examined by SEM and H&E staining after 4 to 7 days of in vitro culturing. To observe the ectopic osteogenic capacity, four 10mmx5mmx2mm cell/scaffold complexes (fdDBM, TCP, CH200, CH500) and a blank control scaffold (fdDBM only) were implanted subcutaneously into each of athymic mice (n=8). The implants were harvested after 9 weeks and H&E stained. Newly formed trabecular bone volume (TBV) was measured by IMAGER-PRO PLUS software, and statistical analysis was performed by ANOVA with SAS software. RESULTS: Canine BMSCs adhered to all 4 types of scaffolds and spread well in their pores 7-8 days after seeding. Athymic subcutaneous ectopic osteogenesis were observed in all the specimens of TCP, CH200, CH500 but were observed only in 75% of BMSCs/fdDBM and 25% of fdDBM. The TCP group showed significant higher TBV percentage (28.2%+/-2.86) than CH200 group (24.1%+/-4.12) and CH500 group (18.1%+/-4.66) (P<0.01). CONCLUSIONS: BMSCs adhered to all 4 scaffolds. When combined with BMSCs, TCP exhibited the greatest osteogenic potential, which indicates that it might be an excellent scaffold material in the field of bone tissue engineering. Supported by National 973 Project (G1999054300) and National Natural Science Foundation of China(30271426).

Animals↗

PubMedDate not supplied

Tumour control probability of stage III inoperable non-small cell lung tumours after sequential chemo-radiotherapy.

UNLABELLED: The aim of this study was to investigate the influence of the duration of waiting time between the end of induction chemotherapy and the start of radiotherapy on tumour control probability (TCP). PATIENTS AND METHODS: Twenty-three patients with inoperable stage III non-small cell lung cancer (NSCLC) received induction chemotherapy followed by radiotherapy. The mean waiting period between the end of induction chemotherapy and the start of radiotherapy was 80 days; in this period, the median tumour volume increased by a factor of about 6. The Poisson model for TCP and the linear-quadratic model were used to calculate changes in TCP in the waiting time. RESULTS: The 2-year survival of patients treated with curative intent was 8%, lower than the mean value of 26% derived from other studies. Assuming that radiotherapy started on the day of restaging or on the first day of radiotherapy (RT1), the calculated mean TCP at restaging was 13.3% and at RT1 was 0.5% for patients treated with curative intent. CONCLUSION: The calculated TCP decreased in the waiting period from 13.3 to less than 1%. Hence, the relatively long interval time between chemo- and radiotherapy had a deleterious effect on local control. We recommend the waiting time to be as short as possible.

Adult↗

PubMed1991

High efficiency reconstitution of a phencyclidine/MK-801 receptor binding site solubilized from rat forebrain membranes.

Phencyclidine (PCP) receptors have been solubilized from rat forebrain membranes with the zwitterionic detergent 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonate. Specific binding of the potent PCP receptor ligands [3H]thienyl-phencyclidine (TCP) and [3H]MK-801 was restored by incorporating extracted membrane protein into lipid vesicles prepared from a total brain lipid extract. A nearly quantitative recovery of solubilized receptor activity was achieved; this was dependent upon both the concentration of detergent used during membrane solubilization and the concentration of added lipid used during the reconstitution. The single, saturable, binding site measured for both [3H]TCP and [3H]MK-801 in solubilized and reconstituted preparations exhibited properties similar to those of the high affinity PCP binding site labeled by these ligands in brain membranes. The ability of ligands selective for this site (MK-801, TCP, and dexoxadrol) to competitively displace specific [3H]TCP binding was retained after solubilization and reconstitution, although IC50 values measured for these ligands were shifted to higher concentrations. Levoxadrol and haloperidol were ineffective at displacing the radioligand binding in both membrane and vesicle preparations. The additive and dose-dependent ability of glutamate and glycine to enhance [3H]TCP binding to the solubilized/reconstituted receptor further suggests that a direct interaction with the N-methyl-D-aspartate receptor/ion channel complex has been preserved in the vesicle preparations. The photoaffinity labeling of two polypeptides (Mr 98,000 and 59,000) by azido-[3H]PCP was demonstrated in the vesicle preparations; this was largely prevented by competitive displacement of the radioligand with PCP before photolysis. These results establish both an essential lipid dependency and polypeptide composition for the high affinity, haloperidol-insensitive, PCP receptor in brain.

Affinity Labels↗

PubMed1991

In vivo delivery of estradiol from ceramic drug delivery devices.

Ceramic drug delivery systems (CDS) are capable of delivering a wide variety of chemicals and/or biologicals directly into the systemic circulation in a continuous manner over long intervals with minimum risk to the recipient. The objectives of the present study were: (i) to determine the capability of tricalcium phosphate (TCP) capsules to deliver estradiol (E) in a sustained manner into the circulation of intact adult male rats, and (ii) to investigate the physiological responses associated with the presence of constant levels of estradiol in adult male rats. Microcrystals, particle size of less than 38 um, of TCP powder were prepared using standard procedures. TCP capsules with an outer diameter of 0.8 cm and an inner diameter of 0.4 cm were prepared by compressing calcined materials in a cylindrical dye at a compression load of 700 Kg. The ceramic capsules had a final density of 1.82 +/- 0.03 gm/cm3. A total of 54 adult male rats were divided into three groups of 18. Each rat in group I was implanted intraperitoneally with 2 CDS, one TCP capsule impregnated with polylactic acid (PLA) and the second nonimpregnated TCP capsule. Each capsule contained 40 mg of E. Animals in group II were implanted with two similar capsules without E (shams) and group III animals which served as intact controls were not fitted with CDS. Eight rats from each group were euthanized 2, 4, or 6 months following CDS implantation. Ceramic capsules were retrieved from the euthanized animals and the amount of E left within the ceramic was determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Characterization of the stimulatory and inhibitory effects of polyamines on [3H]N-(1-[thienyl]cyclohexyl) piperidine binding to the N-methyl-D-aspartate receptor ionophore complex.

Spermidine and spermine, as well as several other structurally related compounds, were tested in a [3H]N-(1-[thienyl]cyclohexyl) piperidine [( 3H]TCP) binding assay to determine the structural requirements of polyamines for activation of the N-methyl-D-aspartate-operated ion channel. Under nonequilibrium conditions, the polyamines enhanced [3H]TCP binding approximately 9-fold, with EC50 values ranging from 0.8 to 60 microM. The order of potency in enhancing [3H]TCP binding was N,N'-bis(3-aminopropyl)-1,3-propanediamine greater than N,N'-bis-(3-aminopropyl)-ethylenediamine greater than spermine greater than spermidine greater than N,N'-bis-(2-aminoethyl)-1,3-propanediamine. 1,3-Diaminopropane produced a partial agonistic effect, whereas putrescine, cadaverine, and 1,7-diaminoheptane were without effect at concentrations up to 1 mM. Eadie-Hofstee analysis of spermidine-induced [3H]TCP binding at equilibrium revealed a 3-fold increase in the affinity without a significant change in receptor density. This was further supported by kinetic data that showed that spermidine produced an increase in the association rate and a decrease in the dissociation rate of [3H]TCP binding to its site. Putrescine, cadaverine, and 1,3-diaminopropane antagonized the effects of spermidine by an apparently noncompetitive mechanism. Magnesium ions mimicked the effects of putrescine, suggesting the possibility that the inhibitory effects of Mg2+ and putrescine are mechanistically related.

Animals↗

PubMed1989

The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites.

Numerous studies have now demonstrated that a binding site for the psychotomimetic drug phencyclidine (PCP) exists within the receptor channel complex for the excitatory amino acid neurotransmitter glutamate, specifically the glutamate receptor selectively activated by N-methyl-D-aspartate (NMDA). Several lines of evidence support the hypothesis that all PCP receptors in rat brain are associated with the NMDA receptor complex. In the present study, we reexamine this hypothesis. We report that the PCP analog [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) labels two high affinity binding sites in membranes prepared from guinea pig brain site 1 (Kd = 14.1 nM, Bmax = 631 fmol/mg of protein) and site 2 (Kd = 46.5 nM, Bmax = 829 fmol/mg of protein). (+)-5-Methyl-10 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate bound to site 1 with high affinity (Kl = 3.2 nM) and to site 2 with low affinity (Kl = 5208 nM). The order of potency of drugs for inhibiting [3H]TCP binding to site 1 correlated with their ED50 values for inhibition of NMDA-mediated responses reported in the literature, whereas the order of potency of drugs for inhibiting [3H]TCP binding to site 2 correlated with their ED50 values for inhibition of [3H]dopamine reuptake reported in the literature. Kinetic experiments demonstrated that glutamate, 2-amino-7-phosphonoheptanoic acid, and Mg2+ modulated [3H]TCP binding to site 1 but not site 2. Preincubation of guinea pig striatal membranes with varying concentrations of the high affinity dopamine reuptake inhibitors N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine caused a wash-resistant inhibition of [3H]TCP binding to site 2 but not site 1. Taken collectively, these data demonstrate the existence of a high affinity PCP binding site associated with the dopamine reuptake carrier and raise the possibility that the therapeutic and psychotomimetic effects of PCP in humans are separable and mediated via different binding sites.

Acetylcholine↗

PubMed1987

Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex.

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.

Animals↗

PubMed1988

Effect of beta-tricalcium phosphate in surgically created subchondral bone defects in male horses.

beta-Tricalcium phosphate (TCP) was evaluated as a synthetic bone grafting material in horses. Sixteen horses were randomly assigned to 4 groups of 4 horses. In each horse, an 11-mm by 10-mm circular defect with a smooth margin was created surgically in the weight-bearing surface of both third metacarpal bones (McIII) and the left third metatarsal bone. The defect in the left McIII was filled with TCP, the defect in the right McIII was filled with a mixture of 50% autogenous cancellous bone (ACB) and 50% TCP, and the defect in the left third metatarsal bone was not filled to serve as a control. Nuclear imaging and radiographic evaluation of surgical sites were performed at postsurgical week (PSW) 4 and 13 in group-I horses and at PSW 26, 39, and 52 in groups-II, -III, and -IV horses, respectively. Horses in groups I, II, III, and IV were euthanatized at PSW 13, 26, 39, and 52, respectively, and specimens were harvested for histologic evaluation. Results were compared among treatment methods, as well as among time intervals. The greatest activity at defect sites was seen in group-I horses at PSW 4. Activity counts in limbs of group-I horses at PSW 13 and counts in limbs of group-II horses at PSW 26 were not significantly (P less than or equal to 0.05) different. Activity counts in groups-III and -IV horses at PSW 39 and 52, respectively, were less than those in groups I and II. However, there was no significant difference in activity counts between limbs implanted with TCP or ACB:TCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Granular tricalcium phosphate in large cancellous defects.

Tricalcium phosphate (TCP) is a porous ceramic which has biological properties of being non-reactive and resorbable, and acts as a scaffolding for bone ingrowth, undergoing progressive degradation and replacement by bone. Tricalcium phosphate has been shown to be comparable to autogenous bone graft in small periodontal defects. However, orthopedic defects are much larger. This prompted us to review the bone ingrowth potential in large cancellous bone defects (up to 12 cm3) in adult pigs. To quantitate bone ingrowth potential, three skeletally mature pigs had metaphyseal defects created in the tibia and femur of each hind limb, for 12 total sites. Twelve-cc defects in the distal femur and eight cc defects in the proximal tibia were made. Bone curetted was saved to be used as autogenous graft in the control, while the other ipsilateral defect was packed with tricalcium phosphate. Four months following the initial defect, the opposite hind extremity was similarly operated. All animals were sacrificed at nine months. Specimens were imbedded in methyl-methacrylate, cut at 120 microns, and stained. The quantity of regenerated bone was measured by histomorphometric techniques. Qualitative assessment at four months revealed absence of inflammation and TCP surrounded by trabecular bone, which was uniformly viable. There was very little TCP left by nine months. Quantitative analysis revealed the tibias to have a higher percent net bone replacement with TCP as compared to the control (32 percent versus 13 percent). The femoral TCP-filled defects were comparable to autogenous bone (both measured 29 percent).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Continuous delivery of azidothymidine by hydroxyapatite or tricalcium phosphate ceramics.

A ceramic drug delivery system was developed for continuous release of azidothymidine (AZT). Tricalcium phosphate (TCP) and hydroxyapatite (HA) ceramics were used to fabricate ceramic devices. Each group of devices consisted of three replicates. Ceramic and AZT mixtures were compressed at a load of 3000 lbs in a 10 mm diameter die using a hydraulic press. For in vitro studies, vitamin E oil was incorporated in six different ratios in devices containing HA (500 mg) and AZT (250 mg). Each device was suspended in phosphate buffered saline (pH 7.4). Devices containing oil released AZT in significantly lower amounts than devices containing no oil. In vivo studies were conducted with devices composed of homogeneous mixtures of 250 mg AZT and 500 mg TCP with and without vitamin E oil in the following combinations: AZT and TCP (Group I), Oil saturated TCP and AZT (Group II), and AZT pellet inserted in an oil saturated TCP shell (Group III). These devices were implanted subcutaneously in Sprague Dawley rats for two weeks. Group II and III devices delivered AZT at a significantly lower rate than Group I devices. Results of both studies suggest that treatment of ceramic devices with oil decreases the release rate and prolongs the delivery of AZT.

Animals↗

PubMed1995

Interaction of arachidonic acid with ligand binding sites of the N-methyl-D-aspartate receptor in rat hippocampal membranes.

Ararchidonic acid, an important oxygenated metabolites of 20-carbon polyunsaturated fatty acid in cell membrane, has been implicated in potentiating the N-methyl-D-aspartate (NMDA) receptor, receptor of glutamate subtype receptors, mediated neurotransmission. We have tested the possibility that arachidonic acid may directly interact with the NMDA receptor by examining the ligand binding to this receptor/channel complex in hippocampal membrane preparation. Micromolar concentrations of arachidonic acid significantly increased both the association and dissociation of [3H]TCP binding but had no effect on the pre-equilibrated [3H]TCP binding. Arachidonic acid had no effect on the Kd and Bmax of [3H]TCP binding. Arachidonic acid also had no effect on the NMDA-displaced [3H]glutamate binding and [3H]glycine binding. In addition, docosahexanoic acid (DHA) potentiated [3H]TCP binding with similar features. However, oleic acid did not affect [3H]TCP binding. This study indicates that arachidonic acid potentiates the NMDA receptor-mediated response by directly increasing the activation of NMDA receptor-gated ion channel.

Animals↗

PubMed1997

Biochemical analysis associated with HL-60 cells incubated with various ceramic materials.

The purpose of this experiment was to determine the effect of TCP, ALCAP, and HA ceramic particles on the viability and proliferation rate of HL-60 cells in culture. Previous experiments have suggested that growing cell lines such as macrophages, fibroblasts, and endothelial cells on discs made of TCP, ALCAP, and HA induced immunochemical and morphological changes. The effect of ceramic particles (< 38 um) on HL-60 cells in culture have never been investigated. A total of 1 x 10(5) (n = 5) cells were placed in culture with 2 mg of ALCAP, TCP, HA particles, or 10 micrograms/ml lipopolysaccharides (LPS). At the end of 24, 48, and 96 hours, the cells were evaluated morphologically and then counted. The supernatants were collected and biochemical analysis for LDH and immunochemical analysis for cytokines IL-1 was performed. The data from this investigation revealed the following: (1) At the end of the 24 hour phase, the cell number in wells containing HA and ALCAP particles were lower than the control cells, whereas cells in the presence of TCP were similar to the control. (2) Microscopic evaluation of cells treated with HA showed hydropic change at 24, 48 and 96 hours. (3) At 96 hours, there were no significant changes in cell number between the groups. This phenomenon could be attributed to the depletion of nutrients within the wells or possibly the cells reaching confluence. (4) The ease of ingestion of macrophages to CPB is as follows: TCP > ALCAP > HA. (5) Biochemical analysis of markers for cellular disturbances revealed that there were no significant differences between the different group at any time point (p < 0.05).

Aluminum Compounds↗

PubMed1998

HIV-1 gp120 envelope protein and morphine-tubular cell interaction products modulate kidney fibroblast proliferation.

BACKGROUND: Renal interstitial scarring is an important feature of HIV-associated nephropathy. Intravenous drug abuse has been demonstrated to be a risk factor for the development of HIV-associated nephropathy in patients with HIV infection. We studied the effect of tubular cell-morphine and/or HIV-1 gp120 envelope protein interaction products on kidney fibroblast (KF) proliferation and apoptosis. METHODS: Tubular cell-morphine and/or gp120 interaction products were prepared by incubating confluent human proximal tubular cells with buffer (TCP), morphine (10(-3) mol/L) (TCM-IP), gp120 (0.01 microgram/mL)(TC-120IP), or morphine (10(-3) mol/L) + gpl20 (0.01 microgram/mL) (TCM-120IP). To evaluate the effect of tubular cell interaction products (TCIP) on KF proliferation, growth arrested kidney fibroblasts were treated with variable concentrations (5%, 10%, 20%, 30%, and 50%) of TCP, TCM-IP, TC-120IP, or TCM-120IP for 48 hours. To evaluate the role of cytokines in TCIP-induced KF proliferation, cells were incubated with TCIP with or without cytokine neutralizing antibodies to TGF-beta, TNF-alpha, FGF, or IL-6 for 48 hours. Subsequently, cells were counted in a hemocytometer (n = 3). To evaluate the effect of TCIP on KF apoptosis, cells were treated with 50% TCP, 50% TCM-IP, 50% TC-120IP, or 50% TCM-120IP for 24 hours and stained with H-33342 and propidium iodide. In parallel experiments KFs were harvested under identical conditions, DNA was isolated and run on gel electrophoresis. To evaluate the role of early growth genes in TCM-120-induced KF proliferation, TCM-120IP-treated cells were probed with cDNA for c-fos and c-jun. RESULTS: TC-120IP at a lower concentration (20%) enhanced (P < 0.001) proliferation of KF when compared with TCP. TCM-IP did not stimulate KF proliferation. On the contrary, TCM-120IP at a lower concentration (20%) promoted (P < 0.001) KF proliferation when compared with TCP, TCM-IP and TC-120IP. TCM-120IP at a lower concentration (20%) also enhanced KF mRNA expression of c-fos and c-jun. TCM-120IP enhanced KF proliferation in a dose-dependent manner. All tubular cell interaction products at a higher concentration (50%) promoted apoptosis of KF. CONCLUSIONS: Tubular cell-gp120 interaction products stimulated KF proliferation. Morphine amplified the effect of tubular cell-gp120 interaction on the proliferation of KF. TCM-120IP-induced KF proliferation may be mediated through the expression of early growth genes; whereas TCM-120IP-induced KF growth suppression may be mediated through the induction of apoptosis.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Expression patterns of chaperone proteins in cerebral cortex of the fetus with Down syndrome: dysregulation of T-complex protein 1.

Chaperone proteins reduce stress-induced denaturation and aggregation of intracellular proteins and exert protective actions by interfering with the stress-induced apoptotic pathway in the neuronal cells. Although many studies have focused on the critical role of chaperones in protein folding and their relevance in protein conformational diseases such as Alzheimer's disease (AD) and prion disease, limited information is available on their expression pattern in AD-related disease, Down Syndrome (DS). In a previous study, we reported differentially expressed molecular chaperone proteins in the brains of adult DS patients. This report demonstrated the relevance of the aberrant expression patterns to biochemical and neuropathological abnormalities in adult DS brain. To investigate whether this aberrant expression patterns already exist in second trimester DS brain, we performed two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-associated laser desorption ionization mass spectroscopy (MALDI-MS) using fetal DS brain. We unambiguously identified and quantified twelve heat shock proteins (HSPs), three glucose regulated proteins (GRPs) and eight T-complex 1 (TCP-1) subunits. Unlike in adult brain with DS, these studies provide evidence for the normal response of most molecular chaperone proteins at the given time point of DS brain development. However, chaperonin protein TCP-1 alpha and beta subunits showed a significant decrease (P < 0.05) in second trimester brain with DS. Comparable response of chaperone proteins in fetal DS brain suggests that not heat-shock induced proteins but rather chaperonin protein TCP-1 may contribute significantly to neuropathogenesis in the early second trimester DS brain. This study extends observations of distinct expression patterns of molecular chaperones in DS brain and we discuss the relevance of aberrant TCP-1 expression patterns to developmental DS brain at the early stage.

Cerebral Cortex↗

PubMed2000

The molecular mechanism of dopamine-induced apoptosis: identification and characterization of genes that mediate dopamine toxicity.

Parkinson's disease (PD) is a progressive neurological disorder caused by rather selective degeneration of the dopaminergic (DA) neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral neuronal loss is still enigmatic and treatment is basically symptomatic. The current major hypothesis suggests that nigral neuronal death in PD is due to excessive oxidative stress generated by auto- and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin and presence of high concentrations of iron. We have found that DA toxicity is mediated through its oxidative metabolites. Whereas thiol-containing antioxidants provided marked protection against DA toxicity, ascorbic acid accelerated DA-induced death. Using the differential display approach, we sought to isolate and characterize genes whose expression is altered in response to DA toxicity. We found an upregulation of the collapsin response mediator protein (CRM) and TCP-1delta in sympathetic neurons, which undergo dopamine-induced apoptosis. The isolation of these genes led us to examine the expression and activity of CRM and TCP-1delta related genes. Indeed, we found a significant induction of mRNAs of the secreted collapsin-1 and the mitochondrial stress protein HSP60. Antibodies directed against collapsin-1 provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. In a parallel study, using antisense technology, we found that inhibition of TCP-1delta expression significantly reduced DA-induced neuronal death. These findings suggest a functional role for collapsin-1 and TCP-1delta as positive mediators of DA-induced neuronal apoptosis.

Animals↗