Anomalous origin of the left main coronary artery from the main pulmonary artery in a young adult.
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Adult↗
Biomedical subjects
W H Liu
Publications and source records attributed to W H Liu.
Modulation of NMDA receptor function by ketamine and magnesium: Part I.
UNLABELLED: N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects of Mg2+, racemic ketamine and its isomers, and the combination of Mg2+ and S(+)-ketamine on NMDA signaling were determined. Mg2+ and ketamine alone inhibited NMDA receptors noncompetitively (half-maximal inhibitory effect concentration: Mg2+ 4.2 +/- 1.2 x 10(-)(4) M at NR1/NR2A and 6.3 +/- 2.4 x 10(-)(4) M at NR1/NR2B; racemic ketamine 13.6 +/- 8.5 x 10(-)(6) M at NR1/NR2A and 17.6 +/- 7.2 x 10(-)(6) M at NR1/NR2B; S(+)-ketamine 4.1 +/- 2.5 x 10(-)(6) at NR1/NR2A and 3.0 +/- 0.3 at NR1/NR2B; R(-)-ketamine 24.4 +/- 4.1 x 10(-)(6) M at NR1/NR2A and 26.0 +/- 2.4 x 10(-)(6) M at NR1/NR2B). The combined application of Mg2+ and ketamine decreased the half-maximal inhibitory effect concentration >90% at both receptors. Isobolographic analysis demonstrated super-additive interactions. Ketamine and Mg2+ inhibit responses of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone. IMPLICATIONS: Ketamine and Mg2+ inhibit functioning of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone.
Analgesics↗
Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics.
UNLABELLED: Mg2+ and ketamine interact superadditively at N- methyl-D-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg2+ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 microM on NR1/NR2A, 3.0 microM on NR2/NR2B) and/or Mg2+ (416 microM on NR1/NR2A, 629 microM on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 +/- 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 +/- 0.03 MAC for desflurane, 1.24 +/- 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 +/- 0.12 MAC for isoflurane, 1.22 +/- 0.08 MAC for desflurane, and 1.28 +/- 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg2+, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg2+, S(+)-ketamine, or-most profoundly-both. Therefore, the analgesic effects of ketamine and Mg2+, are likely to be enhanced in the presence of volatile anesthetics. IMPLICATIONS: Clinically relevant concentrations of volatile anesthetics inhibit functioning of N-methyl-D-aspartate receptors expressed recombinantly in Xenopus oocytes. This inhibition is reversible, concentration-dependent and voltage-insensitive, and results from noncompetitive antagonism of glutamate/glycine signaling. In addition, these effects can be potentiated significantly by co-application of either Mg2+, S(+)-ketamine, or--most profoundly--both.
Analgesics↗
A role for the integrin alphavbeta8 in the negative regulation of epithelial cell growth.
The control of cell growth is regulated through coordinated responses to growth factors and cell-extracellular matrix (ECM) interactions. Integrins, the major family of cell-ECM receptors, are vital to these coordinated responses. Although much is known of the role of integrins in growth promotion, specific examples of integrin-mediated cell growth inhibition are few. On the basis of our findings that the integrin beta8 subunit is expressed in airway epithelial cells and is absent in lung cancers, we investigated the role and mechanism of the integrin alphavbeta8 in mediating growth inhibition. When introduced into either a lung or colon carcinoma cell line, beta8 inhibited cell growth without inducing apoptosis. Ligation of alphavbeta8 also induced cell rounding, inhibited focal contact formation, and initiated an inhibitory signaling pathway as demonstrated by increased expression of the cyclin-dependent kinase inhibitor p21Cip1. The cytoplasmic domain of beta8 was capable of both growth inhibition and causing cell shape changes as shown by the use of a chimeric integrin construct consisting of the beta8-cytoplasmic domain coupled to the beta6-extracellular domain. Finally, when tested in vivo, beta8 potently inhibited tumor growth in nude mice. Together, these results implicate alphavbeta8 as a novel growth-regulatory molecule of epithelial cells.
Actins↗
Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro.
Diabetes of even short duration accelerates the death of capillary cells and neurons in the inner retina by a process consistent with apoptosis. We examined whether the process is accompanied by changes in the expression of endogenous regulators of apoptosis. In postmortem retinas of 18 diabetic donors (age 67 +/- 6 years, diabetes duration 9 +/- 4 years) the levels of pro-apoptotic Bax were slightly, but significantly, increased when compared with levels in 20 age-matched nondiabetic donors (P = 0.04). In both groups, Bax localized to vascular and neural cells of the inner retina. Neither pro-apoptotic Bcl-X(S), nor pro-survival Bcl-X(L) appeared affected by diabetes. The levels of these molecules could not be accurately quantitated in lysates of retinal vessels because of variable degrees of glial contamination. However, studies in situ showed in several pericytes, the outer cells of retinal capillaries, intense Bax staining often in conjunction with DNA fragmentation. Bovine retinal pericytes exposed in vitro to high glucose levels for 5 weeks showed elevated levels of Bax (P = 0.03) and increased frequency of annexin V binding, indicative of early apoptosis. Hence, human diabetes selectively alters the expression of Bax in the retina and retinal vascular pericytes at the same time as it causes increased rates of apoptosis. The identical program induced by high glucose in vitro implicates hyperglycemia as a causative factor in vivo, and provides a model for establishing the role of Bax in the accelerated death of retinal cells induced by diabetes.
Aged↗
Anatomical studies of the urethral plate: why preservation of the urethral plate is important in hypospadias repair.
OBJECTIVE: To describe the detailed anatomy of the urethral plate in relation to its controversial role in hypospadias surgery. MATERIALS AND METHODS: A newborn penis with proximal penile hypospadias and two fetal penises with distal shaft hypospadias were included in the study; 30 normal fetal penises served as the control. Specimens were embedded in paraffin and serially sectioned (6 microm) after formalin fixation. Every 10th section was stained with haematoxylin and eosin. Immunohistochemical staining for nerves (S100), smooth muscles (alpha-actin), blood vessels (factor VIII) and epithelium (cytokeratins 7, 14 and 18) were used on selected sections, with particular attention to the urethral plate. Masson's trichrome and Sirius Red stains were used to localize collagen. RESULTS: There were extensive blood vessels, glands and smooth muscle under the urethral plate in the hypospadias specimens. These relatively well organized tissues corresponded to an abnormally formed corpus spongiosum. The glands underneath the urethral plate and adjacent to the normal urethra showed positive staining for cytokeratins 7 and 18, respectively (markers of endodermal origin) but were negative for cytokeratin 14 (a marker of ectodermal origin). Penile skin and urethral plate epithelium stained positively for cytokeratin 14 but not for cytokeratin 7 and 18. The urethral plate has a rich nerve supply, as determined by S100 staining. Collagen intensity under the urethral plate was no different from that in normal areas. Tunica albuginea stained intensely for type I and III collagen. CONCLUSION: These results show that the urethral plate is well vascularized, has a rich nerve supply and an extensive muscular and connective tissue backing. These features may explain the lower complication rate with onlay flaps than with tube flaps. Therefore, from these anatomical findings, we continue to advocate preservation of the urethral plate and the onlay island flap for hypospadias reconstruction.
Case-Control Studies↗
Anatomy of the neurovascular bundle: is safe mobilization possible?
PURPOSE: We have previously defined the anatomy of the neurovascular bundle in the normal and hypospadiac penis. Historical experience suggests that mobilization of the neurovascular bundle is anatomically possible. We attempt to prove whether mobilization of the neurovascular bundle is safe and theoretically sound. Specific questions that will be addressed are does the neurovascular bundle send perforating branches into the corporal bodies; how far lateral does the dissection need to be before nerves are injured and exactly how deep into Buck's fascia must one go. MATERIALS AND METHODS: A total of 35 normal human fetal penile specimens, gestational age 8 to 35 weeks, and 3 hypospadiac specimens, 33 to 41 weeks of gestation, were serially sectioned and stained with Mason's trichrome and the neuronal markers PGP 9.5 or S100. Computer reconstruction using commercial software and National Institutes of Health imaging allowed 3-dimensional analysis of the nerves, corporal bodies and glans. RESULTS: Perforating nerves into the erectile bodies were not documented along the dorsal or lateral aspect of the tunica in any of the specimens studied. Only in the area of the crural bodies on the ventral lateral surface were nerves noted to pierce into erectile tissue. The neural network was extensive from the 11 and 1 to the 5 and 7 o'clock positions corresponding to the erectile tissue and urethral spongiosum junction. At this junction minor nerve branches were noted to perforate into the urethral spongiosum. A microscopic plane exists between the neurovascular bundle and tunica of the corporal bodies measuring 20 to 30 micro. in specimens greater than 30 weeks in gestation. CONCLUSIONS: Perforating branches from the dorsal lateral neurovascular bundle do not exist based on serial step sectioning and microscopic examination of male genital specimens. Surgically it is possible to elevate the neurovascular bundle but the dissection needs to remain directly on top of the tunica albuginea to prevent neuronal injury. Small perforating branches into the urethral spongiosum may be injured with unknown significance. We continue to advocate plication in the nerve-free zone at the 12 o'clock position for correction of penile curvature.
Fetus↗
Apoptosis regulating genes in neuroendocrine tumors.
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms. They are relatively uncommon and characterised by a relatively indolent clinical course. The indolent nature of NETs has long been enigmatic and recent advances in apoptosis research have led to speculation regarding the role of programmed cell death in NET tumorigenesis. It is hoped that a fundamental molecular understanding will help explain these variant behaviors that are so evident to the clinician, and ultimately yield novel and more effective therapies. Recent studies have demonstrated that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of NETs and that the frequent expression of the BCL-2 oncoprotein in these tumors may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated BCL-2 and c-MYC may be implicated in the multistep tumorigenesis of human NETs. It is also clear that numerous cellular gene products can and will be shown to impact upon apoptosis in NETs; some of these may even be molecules identified as oncoproteins or tumor suppressors. The major challenge will be to ascribe primary pathogenetic significance to tumor-associated derangements in expression of these molecules, and hopefully to then exploit our knowledge toward therapeutic benefit.
Animals↗
Thrombin stimulates MMP-9 mRNA expression through AP-1 pathway in human mesangial cells.
AIM: To investigate the thrombin mediated induction of gelatinase B (MMP-9) in mesangial cells (MC) and the underlying role of activator protein-1 (AP-1). METHODS: Cultured human mesangial cells were exposed to thrombin in the presence or absence of hirudin, curcumin, and c-fos antisense or sense oligonucleotides. Northern hybridization was employed to assess MMP-9 mRNA expression, and electrophoretic mobility shift assay (EMSA) for AP-1 DNA binding activity. RESULTS: The levels of MMP-9 mRNA in the cell treated with different doses of thrombin (500, 1500, and 4500 u/L, respectively) were 1.1, 3.3, and 4.8 times higher than that in the control, respectively. There was also an increase in AP-1 binding activity (3.5, 5.9, and 7.1 fold than that of the control) in accordance with MMP-9 mRNA levels in the presence of thrombin. Hirudin, curcumin, and c-fos antisense oligonucleotides could block thrombin-induced expression of MMP-9 mRNA as well as AP-1 binding activity. CONCLUSION: Thrombin is a potent stimulator of MMP-9 gene expression in human mesangial cells, and the underlying intracellular events are mediated, at least partly, by AP-1 pathway.
Cells, Cultured↗
Nucleophosmin/B23 regulates the susceptibility of human leukemia HL-60 cells to sodium butyrate-induced apoptosis and inhibition of telomerase activity.
Stable clones of HL-60 cells in which nucleophosmin/B23 was over-expressed or down-regulated were established. The nucleophosmin/B23 protein levels in nucleophosmin/B23 over-expressed (pCR3-B23) or down-regulated (pCR3-32B) cells during BuONa/vanadate-induced apoptosis were characterized as compared with control vector-transfected (pCR3) cells. Over-expression of nucleophosmin/B23 resulted in decreased susceptibility of the cells to BuONa/vanadate-induced apoptosis. The response to inhibition of telomerase activity under BuONa/vanadate treatment also decreased in nucleophosmin/B23 over-expressed (pCR3-B23) cells. On the other hand, down-regulation of nucleophosmin/B23 made the cells more susceptible to BuONa-induced apoptosis or inhibition of telomerase activity. More precisely, by serial dilutions of each extract, the telomerase activity of the cells without drug treatment was determined and was found to be higher in nucleophosmin/B23 over-expressed (pCR3-B23) cells and lower in nucleophosmin/B23 down-regulated (pCR3-32B) cells as compared with the control vector-transfected (pCR3) cells. Our results indicate that nucleophosmin/B23 plays a functional role in the control of cellular apoptosis and immortalization.
Apoptosis↗
Effect of glucose on endothelin-1-induced calcium transients in cultured bovine retinal pericytes.
Published work has shown that endothelin-1-induced contractility of bovine retinal pericytes is reduced after culture in high concentrations of glucose. The purpose of the present study was to establish the profile of endothelin-1-induced calcium transients in pericytes and to identify changes occurring after culture in high concentrations of glucose. Glucose had no effect on basal levels of cytosolic calcium or on endothelin-1-induced calcium release from intracellular stores. However, influx of calcium from the extracellular medium after endothelin-1 stimulation was reduced in pericytes that had been cultured in 25 mM D-glucose. L-type Ca(2+) currents were identified by patch clamping. The L-type Ca(2+) channel agonist, (-)-Bay K8644, caused less influx of calcium from the extracellular medium in pericytes that had been cultured in 25 mM D-glucose than in those cultured with 5 mM D-glucose. However, 3-O-methylglucose, a nonmetabolizable analogue of glucose which can cause glycation, had similar effects to those of high concentrations of glucose. The results suggest that reduced function of the L-type Ca(2+) channel that occurs in bovine retinal pericytes after culture in high concentrations of D-glucose is probably due to glycation of a channel protein.
Animals↗
Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosmin/B23 and telomerase activity.
The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 microg/ml, 24 to 96 hr) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 overexpressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector-transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 microg/ml berberine for 48 to 96 hr. DNA extracted from pCR3 cells contained more fragmented DNA than pCR3-B23 cells during treatment with 15 microg/ml berberine for 24 to 48 hr. Our results indicate that berberine-induced apoptosis is associated with down-regulation of nucleophosmin/B23 and telomerase activity. We also suggest that nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction.
Apoptosis↗
Decrease in nucleophosmin/B23 mRNA and telomerase activity during indomethacin-induced apoptosis of gastric KATO-III cancer cells.
The mRNA expression of nucleophosmin/B23 in gastric cancers (T) and the matched adjacent "normal" gastric mucosa (N) obtained from patients without any preoperative treatment were determined. Telomerase activity was detected in tumor tissues from six of seven patients. Analysis of the adjacent "normal" gastric mucosa in the same patients revealed all seven were negative for telomerase activity. In comparing clinical data for all seven patients, the stages of cancer seemed to be associated with T/N nucleophosmin/B23 mRNA expression. Cancers of later stages seemed to have higher T/N nucleophosmin/B23 mRNA ratio. After 3-4 days of 1 mM indomethacin treatment about 60-85% of gastric cultured KATO III cancer cells exhibited the features with highly condensed nuclei and decrease in cell size. Concomitant with the increase in the percentage of KATO III cells exhibiting the morphological features of apoptosis, there was a decrease in the viability of cells as determined by exclusion of trypan blue. A decline in telomerase activity in indomethacin-treated versus untreated cells was observed over times (2-4 days). The steady-state level of nucleophosmin/B23 mRNA, as determined by the levels of radioactivity of the hybridizing bands also decreased during the indomethacin treatment. At some times after the removal of indomethacin, cell growth and telomerase activity resumed in little extent (approx. 60%). When nucleophosmin/B23 antisense oligonucleotide was included in the cell culture upon removal of indomethacin, virtually no recovery of cell growth and telomerase activity were observed.
Apoptosis↗
Anatomical studies of the human clitoris.
PURPOSE: Endogenous or exogenous testosterone exposure to the fetus during gestation may result in masculinization of the external genitalia. Surgical correction requires a clear understanding of normal female anatomy. We report observations from our anatomical dissections on which we base our approach to reduction clitoroplasty. MATERIALS AND METHODS: A total of 14 normal human fetal clitoral specimens at 8 to 24 weeks of gestation were serially sectioned after formalin fixation. Every tenth section was stained with Masson's trichrome, smooth muscle alpha-actin and the neuronal markers PGP 9.5 or S-100. Computer reconstruction using imaging software permitted 3-dimensional analysis of the nerves, corporeal bodies and glans clitoris. These specimens were compared with 2 obtained postnatally at feminizing genitoplasty. RESULTS: The normal fetal clitoris consists of 2 corporeal bodies with a midline septum. The ultrastructure of the female corporeal bodies is similar to that of the male counterpart. The glans clitoris forms a cap on top of the distal end of the narrowed corporeal bodies. There is a midline septum starting on the ventral aspect and extending approximately halfway into the glans. Large bundles of nerves course along the corporeal bodies with the highest density on the dorsal aspect or top. No nerves were noted at the 12 o'clock position, although nerves extend completely around the tunica in a fashion similar to that of the fetal penis. Glans innervation is provided by multiple perforating branches entering at the dorsal junction of the corporeal body and glans. The lowest density of nerves in the glans is on the ventral aspect in juxtaposition to the glans septum. In surgical specimens obtained from patients with congenital adrenal hyperplasia nerves were adjacent to the excised tunica of the corporeal bodies, especially on the lateral aspect. CONCLUSIONS: A clear understanding of the anatomy of the human clitoris is important for surgical reconstruction. As in the human penis, nerves in the clitoris form an extensive network around the tunica of the corporeal body with a nerve-free zone at the midline 12 o'clock position. Care should be taken to preserve all nerves. Reduction of the glans clitoris should not violate the extensive innervation that predominates on the dorsal aspect of the glans. The normal clitoris has corporeal bodies that are smaller but analogous to those of the penis. One may consider their function when extensive resection is considered.
Clitoris↗
DNA binding studies of a solvatochromic fluorescence probe 3-methoxybenzanthrone.
A fluorescence probe of 3-methoxybenzanthrone (MBA) exhibits significant solvatochromic characteristics correlated with the polarity of solvents. The interaction of the solvatochromic fluorescence probe with calf thymus DNA (ct-DNA) has been investigated. In the presence of ct-DNA the fluorescence of MBA is strongly quenched with a blue-shift of emission peak and a hypochromism in absorption spectra. The absorption spectra, fluorescence quenching and fluorescence polarization experiments show that the MBA molecule as an intercalator is inserted into the base-stacking domain of the ct-DNA double helix, and the interaction of the nucleobases with the MBA molecule causes quenching of fluorescence and hypochromism in the absorption spectra. The intrinsic binding constant and the binding site number were determined to be 1.70 x 10(5) mol l-1 in base pairs and six, respectively. The I0/I versus [ct-DNA] plot shows linear relationship in the range covering 4.3 x 10(-7)-1.02 x 10(-4) mol l-1 in base pairs which can be used for ct-DNA determination. The limit of detection was found to be 4.3 x 10(-7) mol l-1 in base pairs (0.5 microgram ml-1).
Absorption↗
Mortalization of human promyelocytic leukemia HL-60 cells to be more susceptible to sodium butyrate-induced apoptosis and inhibition of telomerase activity by down-regulation of nucleophosmin/B23.
Vanadate (10 microM), a potent inhibitor of tyrosine phosphatase, added simultaneously potentiated BuONa-induced (1 mM) apoptosis. The steady-state level of nucleophosmin/B23 mRNA and the total cellular nucleophosmin/B23 protein decreased during the BuONa/vanadate-induced apoptosis. Stabilization and promotor transcriptional activity assays indicate that the decrease in nucleophosmin/B23 mRNA in BuONa/vanadate-treated HL-60 cells was transcriptionally regulated. A decline in telomerase activity was observed in HL-60 cells treated with BuONa/vanadate for 24-96 h. There was virtually no decline of nucleophosmin/B23 mRNA nor the telomerase activities during the growth arrest by serum-starvation. The decrease in nucleophosmin/B23 mRNA expression and telomerase activity in HL-60 cells subsequent to BuONa/vanadate treatment can thus be attributed to cellular apoptosis rather than the growth arrest induced by BuONa/vanadate. Nucleophosmin/B23 antisense oligomer treatment significantly potentiated BuONa-induced apoptosis and inhibition of telomerase activity. Results of this study suggest that nucleophosmin/B23 is one of the key elements in the down-regulation of nucleolar function for cellular apoptosis and mortalization.
Apoptosis↗
TFF1 gene expression in human medullary thyroid carcinoma.
Medullary thyroid carcinoma (MTC) is an uncommon tumour of calcitonin-secreting C-cells of the thyroid gland. This cancer represents an important potential model for the study of mechanisms of human epithelial cell transformation. Although recent studies have identified the gene involved in familial forms of MTC, little is known about the molecular pathogenesis of the sporadic variants of this tumour. The biological and prognostic significance of TFF1 expression, particularly in diverse human malignancies, suggests that the TFF1 protein could have a role in human neoplasia. Furthermore, in prostate cancer it has been demonstrated that TFF1 expression is closely associated with premalignant changes and neuroendocrine differentiation. In the present study, the expression of TFF1 was analysed in 18 human MTCs, comprising sporadic and familial tumours, C-cell hyperplasia, and one case of lymph gland metastasis. TFF1 expression was also examined in the cultures of a human MTC-derived tumour cell line (TT cell line). The results showed that ten sporadic tumours, three hereditary tumours (including C-cell hyperplasia), and one lymph gland metastasis displayed TFF1 immunoreactivity. Indirect fluorescence immunocytochemistry and Western blotting revealed that the TFF1 protein was strongly expressed in the TT cells. Northern analysis revealed that tumours and TT cells expressed the TFF1 transcript. Although the function of TFF1 protein in the carcinogenesis of MTC remains to be elucidated, its expression in the majority of cases of both sporadic and hereditary tumours, metastatic tumours, and in C-cell hyperplasia suggests that it may contribute to the pathogenesis of MTC.
Adolescent↗
Glucose-induced oxidative stress in vascular contractile cells: comparison of aortic smooth muscle cells and retinal pericytes.
Free radical-mediated damage to vascular cells may be involved in the pathogenesis of diabetic vasculopathy. The aim of this study was to compare the extent of glucose-induced oxidative stress in both vascular smooth muscle cells (VSMCs) and pericytes and the effect on antioxidant enzyme gene expression and activities. Porcine aortic VSMC and retinal pericytes were cultured in either 5 or 25 mmol/l glucose for 10 days. Intracellular malondialdehyde (MDA) was measured as a marker of peroxidative damage, and mRNA expression of CuZn-SOD, MnSOD, catalase, and glutathione peroxidase (GPX) were measured by Northern analysis. Glutathione (GSH) was also measured. There was a significant increase in MDA in VSMCs in 25 mmol/l glucose (1.34 +/- 0.11 vs. 1.88 +/- 0.24 nmol/mg protein, 5 vs. 25 mmol/l D-glucose, mean +/- SE, n = 15, P < 0.01), but not in pericytes (0.38 +/- 0.05 vs. 0.37 +/- 0.05 nmol/mg protein, n = 11). There was a significant decrease in GSH in both cell types (VSMC, 1.40 +/- 0.13 vs. 0.69 +/- 0.12 nmol/mg protein, n = 15, P < 0.001; pericytes, 1.97 +/- 0.17 vs. 0.94 +/- 0.16 nmol/mg protein, n = 11, P < 0.001). mRNA expression of CuZnSOD and MnSOD was increased only in VSMCs (by 58.5 +/- 8.1 and 41.0 +/- 6.9%, respectively, n = 8, P < 0.01). CuZnSOD protein was increased by approximately 120% (P < 0.00001). None of the antioxidant enzyme activities was altered between 5 and 25 mmol/l glucose in either cell type. Both MnSOD activities and GSH concentrations were higher in pericytes compared with VSMC under basal (5 mmol/l) conditions (P < 0.05 and P < 0.02, respectively). These results demonstrate glucose-induced reduction of GSH in both cells, but only in VSMC is there evidence of oxidant damage in the form of lipid peroxidation, implying significant differences in intracellular responses to glucose between contractile cells in the macro- and microvasculature.
Animals↗