Biomedical subjects

Hui Yan

Publications and source records attributed to Hui Yan.

At least 37 records · Page 2Linked to original sources

PubMed2005

[Effect of a new gasotransmitter, hydrogen sulfide, on collagen remodeling of pulmonary artery under hypoxia].

OBJECTIVE: To study the modulatory effect of hydrogen sulfide (H(2)S) on the accumulation of collagen type I and type III in the wall of pulmonary small artery during hypoxic pulmonary vascular remodeling. METHODS: Nineteen male Wistar rats were randomly divided into a control group (n = 6), a hypoxic group (n = 7) and a hypoxia + NaHS group (n = 6). Hypoxic challenge was performed everyday for 21 days. NaHS solution was injected peritoneally everyday before hypoxia challenge for rats in the hypoxia + NaHS group. After 21 days of hypoxia, the mean pulmonary artery pressure was measured by pulmonary artery catheterization. The weight ratio of right ventricle to left ventricle + septum [RV/(LV + SP)] was also measured. The plasma level of H(2)S was determined by methylene blue spectrophotometric method. The expression of collagen type I and type III in pulmonary small arteries were detected by immunohistochemistry. The expression of procollagen type I and type III mRNA in pulmonary small arteries were detected by in situ hybridization. RESULTS: (1) Compared with the control group, the mPAP increased by 46% (P < 0.01), the weight ratio of RV/(LV + SP) increased by 41% and the plasma level of H(2)S decreased by 36% for rats in the hypoxia group (P < 0.01). Compared with the hypoxia group, the mPAP decreased by 31% (P < 0.01), the weight ratio of RV/(LV + SP) decreased by 24% and the plasma level of H(2)S increased by 65% (P < 0.01) for rats in the hypoxia + NaHS group. (2) Expression of collagen type I in small and median pulmonary arteries of the three groups: compared with rats in the control group, collagen type I expression increased by 81% and 62% respectively for rats in the hypoxia group (P < 0.01); compared with rats in the hypoxia group, the expression decreased by 32% and 18% respectively for rats in the hypoxia + NaHS group (P < 0.01). (3) Expression of procollagen type I mRNA in small and mid pulmonary arteries of the three groups: compared with rats in the control group, the expression increased by 49% and 68% respectively (P < 0.01) for rats in the hypoxia group; compared with rats in the hypoxia group, the expression decreased by 31% and 33% respectively for rats in the hypoxia + NaHS group (P < 0.01). (4) Expression of collagen type III in small pulmonary arteries of the three groups: compared with rats in the control group, the expression increased by 84% for rats in the hypoxia group (P < 0.01); compared with rats in the hypoxia group, the expression decreased by 37% for rats in the hypoxia + NaHS group (P < 0.01). Compared with rats in the control group, the expression of collagen type III in median pulmonary arteries increased by 38% in the hypoxia group (P < 0.01), while there was no significant difference between the hypoxia group and the hypoxia + NaHS group. (5) Expression of procollagen type III mRNA in small and median pulmonary arteries of the three groups: compared with rats in the control group, the expression increased by 53% and 17% respectively (P < 0.01) for rats in the hypoxia group; compared with rats in the hypoxia group, the expression decreased by 45% and 33% respectively for rats in the hypoxia + NaHS group (P < 0.01). CONCLUSIONS: In the process of hypoxic pulmonary vascular collagen remodeling in rats, H(2)S could inhibit the abnormal accumulation of collagen type I and type III in the wall of pulmonary small arteries. This effect may be one of the mechanisms by which H(2)S ameliorates hypoxic pulmonary vascular remodeling.

Animals↗

PubMed2004

Neural cells in the esophagus respond to glial cell line-derived neurotrophic factor and neurturin, and are RET-dependent.

Glial cell line-derived neurotrophic factor (GDNF) is expressed in the gastrointestinal tract of the developing mouse and appears to play an important role in the migration of enteric neuron precursors into and along the small and large intestines. Two other GDNF family members, neurturin and artemin, are also expressed in the developing gut although artemin is only expressed in the esophagus. We examined the effects of GDNF, neurturin, and artemin on neural crest cell migration and neurite outgrowth in explants of mouse esophagus, midgut, and hindgut. Both GDNF and neurturin induced neural crest cell migration and neurite outgrowth in all regions examined. In the esophagus, the effect of GDNF on migration and neurite outgrowth declined with age between E11.5 and E14.5, but neurturin still had a strong neurite outgrowth effect at E14.5. Artemin did not promote neural migration or neurite outgrowth in any region investigated. The effects of GDNF family ligands are mediated by the Ret tyrosine kinase. We examined the density of neurons in the esophagus of Ret-/- mice, which lack neurons in the small and large intestines. The density of esophageal neurons in Ret-/- mice was only about 4% of the density of esophageal neurons in Ret+/- and Ret+/+ mice. These results show that GDNF and neurturin promote migration and neurite outgrowth of crest-derived cells in the esophagus as well as the intestine. Moreover, like intestinal neurons, the development of esophageal neurons is largely Ret-dependent.

Animals↗

PubMed2004

[Changes and significance of hydrogen sulfide/cystathionine gamma-lyase system in hypertension: an experimental study with rats].

OBJECTIVE: To explore the significance of hydrogen sulfide/cystathionine gamma-lyase (H(2)S/CSE) system in the development of hypertension and the effects of H(2)S/CSE system on the modulation of aortic remodeling process of hypertension. METHODS: Eight 4-week-old male WKY rats were used as WKY control group, and another sixteen SHR rats at the age of 4 weeks were randomly divided into SHR control group (n = 8) and SHR + NaHS (H(2)S donor) group (n = 8). The rats of SHR control and WKY control were injected with normal saline and the rats of the SHR + NaHS group were injected with NaHS each day. Five weeks later, the blood pressure and the left-to-whole heart weight ratio were determined. The transcriptional level of CSE in aorta and the H(2)S level in plasma were detected. The morphometric parameters of the thoracic aorta including the outer radius, medium area and ratio of wall thickness to lumen radius were detected too. RESULTS: At the age of 9 weeks the systolic blood pressure and the left-to-whole heart weight ratio of the SHR control rats were both higher than those of the WKY control rats [(184 +/- 12) mm Hg vs (108 +/- 23) mm Hg, 1 mm Hg = 0.133 kPa, and (0.853 +/- 0.021) vs (0.826 +/- 0.024)]. The transcriptional level of CSE in aorta and the H(2)S level in serum of the rats in the SHR control group were both lower than those of the rats in the WKY control group (9.3 +/- 0.7) x 10(-8) fmol vs (16.1 +/- 1.0) x 10(-8) fmol, and (20 +/- 9) micro mol/L vs (48 +/- 13) micro mol/L, while the morphometric parameters of the thoracic aorta including the outer radius, the medium area and ratio of lumen radius and wall thickness of the SHR control rats were all higher compared with those of the WKY control rats [outer radius: (1999 +/- 45) micro m vs (1790 +/- 96) micro m], medium area: (0.60 +/- 0.06) mm(2) vs (0.48 +/- 0.03) mm(2), and ratio of wall thickness to lumen radius: (0.066 +/- 0.006) vs (0.060 +/- 0.004). The exogenous administration of NaHS made the systolic blood pressure of rats in the SHR + NaHS group much lower than that of the rats in SHR control group [(158 +/- 13) mm Hg vs (184 +/- 12) mm Hg], however, the transcriptional level of CSE in aorta and the H(2)S level in serum of the rats in SHR + NaHS group were much higher than those of the rats in SHR control group [(12.4 +/- 1.0) x 10(-8) fmol vs (9.3 +/- 0.7) x 10(-8) fmol] vs [(96 +/- 32) micro mol/L vs (20 +/- 9) micro mol/L]. The morphometric parameters of SHR + NaHS group were lower than those of the SHR control group. CONCLUSION: Down regulation of H(2)S/CSE system is a major factor in the development of spontaneous hypertension and the accompanying structural remodeling of aorta. Exogenous administration of H(2)S may attenuate the process of hypertension.

Animals↗

PubMed2004

[Possible effects of endogenous hydrogen sulfide on aortic remodeling in hypertensive rats].

OBJECTIVE: To explore the role and the possible mechanism of hydrogen sulfide (H(2)S) in modulating the remodeling of aorta of hypertensive rats. METHODS: Twenty-four male WKY rats were randomly divided into WKY control group, WKY+NaHS (H(2)S donor) group and WKY+PPG group. Another twenty-four male SHR rats at the age of 4 weeks were also divided into SHR control group, SHR+NaHS group and SHR+PPG group. SHR control and WKY control rats were injected with water, rats of SHR+NaHS group and WKY+ NaHS group were injected with NaHS, rats of SHR +PPG group and WKY +PPG group were injected with PPG each day. Five weeks later, the blood pressure was determined. The rat aortas were dyed with Weigert's Method. The morphometric parameters including outer radius, lumen radius and the media area were calculated by Leica workstation. The proliferation of smooth muscle cells was detected by immunohistochemical assay of PCNA. RESULTS: The morphometric parameters of outer radius, lumen radius, medium area, and the ratio of wall thickness to lumen radius in SHR control rats were all higher than those of WKY control rats [outer radius (1 999+/-45) microm vs (1 790+/-96) microm, lumen radius(1 759+/-91) microm vs (1 636+/-94) microm, medium area (0.60+/-0.06) microm(2) vs (0.48+/-0.03) microm(2), and the ratio of wall thickness to lumen radius (0.066+/-0.006) vs (0.060+/-0.004)]. Expression of PCNA in aorta of SHR control rats was higher than that of WKY control rats too. Most of the structural remodeling parameters decreased in the rats of SHR+NaHS group [outer radius(1 864+/-66) microm, lumen radius (1 634+/-66) microm, medium area (0.53 +/-0.06) microm(2)] compared with those in rats of SHR control group. Expression of PCNA in aorta of SHR+NaHS control rats decreased compared with that of SHR control rats at the same time. CONCLUSION: H(2)S is one of the key factors playing important roles in the modulation of the structural remodeling in aorta of SHR rats. Exogenous administration of H(2)S may attenuate the development of hypertensive rat aorta remodeling effectively.

Animals↗

PubMed2004

XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters.

Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. The prodrug demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of (14)C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of (3)H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.

Amines↗

PubMed2004

[Expression of connexin in atrium of patients with atrial fibrillation and its signal transduction pathway].

OBJECTIVE: To explore the expression of connexin (Cx) and its signal transduction pathway in the atrium of patients with atrial fibrillation (AF). METHODS: Atrial tissue samples of 63 patients undergoing cardiac surgery, including patients with chronic AF or paroxysmal AF (PAF), and those with sinus rhythm, were collected during operation. The mRNA expressions of calcineurin B and mitogen-activated protein kinase-1 (MKP-1) were detected by semi-quantitative RT-PCR. The protein expressions of extracellular-signal regulated kinase 1 (ERK1), phospho-ERK1 (P-ERK1), Cx40 and Cx43 were analyzed by Western blotting. HE staining and immunohistochemistry were used to examine the distribution of Cx40 and Cx 43. RESULTS: Increased amounts of Cx40 protein (left atrium: 2.2 +/- 0.8, 2.2 +/- 0.6; right appendages: 2.1 +/- 0.5, 2.0 +/- 0.8) were found in the left atrium and right appendages of patients with Chronic persistent AF (CAF) or paroxysmal AF (PAF) (P < 0.05). The expression of Cx43 was only increased in the left atrium of patients with CAF and PAF (3.1 +/- 0.6, 2.8 +/- 0.7 vs 1.0 +/- 0.2, both P < 0.05). The amounts of Calcineurin B mRNA, MKP-1 mRNA and P-ERK1 of patients with CAF or PAF were significantly increased compared with patients in sinus rhythm (P < 0.05). Immunohistochemistry revealed that Cx40 and Cx43 of CAF patients and PAF patients acculmated in the intracellular site, and at the lateral member of atrial cells, both connexins redistributed. CONCLUSION: The increased expression and disorderly distribution of Cx 40 and Cx 43 protein in the atrium of AF patients may be related with the abnormal activation and disequilibria of regulation of ERK1, MKP-1 and calcineurin.

Adult↗

PubMed2004

The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats.

Hydrogen sulfide (H(2)S) is a newly found modulator in vascular system. This work showed that gene expression of cystathionine gamma-lyase (CSE), a H(2)S generating enzyme, and the activity of CSE in thoracic aorta were suppressed in hypertension rats. The plasma level of H(2)S also decreased in those rats. Exogenous administration of H(2)S could increase the plasma level of H(2)S and enhance the CSE activity of aorta. Exogenous administration of H(2)S also attenuated the elevation of pressure and lessened the aorta structural remodeling during the development of hypertension. In WKY rats, the gene expression and activity of CSE also decreased when the endogenous production of H(2)S was deprived by administration of DL-propargylglycine (specific inhibitor of CSE), accompanying the elevated pressure and the development of vascular remodeling. The results showed that endogenous H(2)S system was involved in both the maintenance of basal blood pressure and the development of hypertension. Exogenous H(2)S could exert beneficial effect on the pathogenesis of spontaneous hypertension.

Alkynes↗

PubMed2004

A quantitative method for measuring gene expression magnitude and volume delivered by gene therapy vectors.

This study describes a quantitative method to measure the magnitude and distribution of gene expression following local delivery of an adenoviral vector containing the human sodium iodide symporter (hNIS) reporter gene into the canine prostate. Following systemic administration of Na(99m)TcO(4), autoradiographs of prostate sections depicting hNIS-dependent (99m)TcO(4)(-) uptake were digitized and stacked to produce a three-dimensional reconstruction of gene expression. Frequency histograms reflecting hNIS gene expression magnitude and volume were used to quantify hNIS function. The method demonstrated submillimeter resolution allowing for precise measurements of gene expression magnitude and volume in vivo. The method developed here could be applied to other reporter gene systems in which the readout can be digitized from thin tissue sections.

Adenoviridae↗

PubMed2004

Image-guided procedures for intensity-modulated spinal radiosurgery. Technical note.

Radiosurgery for brain tumors has been well established in the radiation oncology and neurosurgery fields. Radiosurgery of extracranial tumors such as those involving the spine is, however, still in the early stage because of difficulties in patient immobilization and organ motion. The authors describe an image-guided procedure for intensity-modulated spinal radiosurgery that was developed at Henry Ford Hospital.

Algorithms↗

PubMed2004

[Interaction between endogenous nitric oxide and hydrogen sulfide in pathogenesis of hypoxic pulmonary hypertension].

OBJECTIVE: To investigate the interaction between nitric (NO) / nitric oxygenase (NOS) and hydrogen sulfide (H(2)S)/ cystathionine-gamma-lyase (CSE) system in the pathogenesis of hypoxic pulmonary hypertension. METHODS: 25 rats were randomly divided into four groups: hypoxic group (n=7 ), hypoxic + L-NAME group (n=6 ), hypoxic + PPG group (n=6) and control group (n=6 ). After 21 days, pulmonary artery mean pressure (mPAP) of each rat was evaluated, and the plasma concentration of H(2)S and NO was measured. Meanwhile, the activities of CSE in pulmonary tissue in hypoxic, hypoxic + L-NAME and control groups were detected, respectively, and expressions of NOS in pulmonary arteries in hypoxic, hypoxic + PPG and control groups were also detected by immunohistochemistry technique. RESULTS: mPAP was significantly increased in hypoxic rats as compared with normal controls. Meanwhile, compared with controls, the production of NO and H(2)S in plasma, the activity of CSE in pulmonary tissue and expression of NOS in pulmonary arteries were markedly decreased in hypoxic rats. However, mPAP was significantly increased in hyopxic + L-NAME group as compared with hypoxic groups, and at the same time, the plasma concentration of NO was markedly decreased. However, the plasma concentration of H(2)S and the activity of CSE in pulmonary tissue in hyopxic+L-NAME group were increased significantly as compared with those of hypoxic group. PPG also worsened pulmonary hypertension of hypoxic rats, however,it increased endogenous production of NO and the expression of NOS of pulmonary arteries obviously. CONCLUSION: There is a negative feed back effect between NO/NOS system and H(2)S/CSE system in development of hypoxic pulmonary hypertension. They might interact with each other and therefore play an important regulating role in hypoxic pulmonary hypertension.

Animals↗

PubMed2004

[Hydrogen sulfide: a novel cardiovascular functional regulatory gas factor].

Hydrogen sulfide (H(2)S) may be endogenously produced by cystathionine beta-lyase (CBS) and cystathionine gamma-lyase (CSE) as a cardiovascular physiological functional factor. On the hypoxic pulmonary hypertension (HPH) animal model, the plasma H(2)S concentration, the gene expression and the activity (CSE) were decreased in lung tissues In L-NAME induced hypertension and spontaneous hypertension rats (SHR) models, the plasma H(2)S concentration, vascular CSE activity and mRNA expression were obviously decreased. When H(2)S was exogenously supplied, systolic pressure obviously decrease. These studies suggested that CSE/H(2)S pathway participated in the pathophysiological development of hypertension. The endogenous level of H(2)S produced by some arterial tissues increased in both septic and endotoxic shock rats. The level of H(2)S highly correlated with the endogenous level of NO. These results suggest that H(2)S may be a novel cardiovascular functional regulator.

Animals↗

PubMed2004

[Efficient soluble expression, purification and identification of the truncated SAG1 gene of Toxoplasma gondii in Escherichia coli].

OBJECTIVE: To express truncated SAG1 gene in Escherichia coli to obtain purified recombinant SAG1, and identify the immunoreactivity of the product. METHODS: The plasmid pET-30a(+)-trSAG1 was constructed, which was cut by Nco I and HindIII to obtain truncated SAG1 gene and inserted into pET-32a(+) cut by the same two restriction enzymes. After identification by restriction enzymes, the plasmid pET-32a(+)-trSAG1 was transformed into E.coli BL21, and the soluble product induced by 0.1 mmol/L IPTG for 4 hour before purification with Ni-NTA agarose, followed by identification of the purified recombinant protein with SDS-PAGE, Western-blotting and ELISA. RESULTS: Recombinant pET-32a(+)-trSAG1 was successfully constructed and high level of truncated SAG1 expression achieved in E.coli. SDS-PAGE showed that the expressed protein was approximately 40,000 in size and expressed in a soluble form that could be easily purified by Ni-NTA agarose. Western-blotting demonstrated that the purified product could be specifically recognized by sera from rabbits immunized with native antigen of T.gondii, and could also be recognized, as shown by ELISA, by sera from human with T.gondii infection. CONCLUSIONS: The truncated SAG1 gene was successfully expressed in E.coli in a soluble form, and the recombinant protein may be of value in the diagnosis of toxoplasmosis.

Animals↗

PubMed2004

[Changes of endogenous hydrogen sulfide (H2S) in hypertensive rats].

OBJECTIVE: Hydrogen sulfide, a well known toxic gas, has been found to play important roles in many organs and tissues, especially in cardiovascular system recently. The aim of this study was to explore the producing rate of hydrogen sulfide (H(2)S) in aorta and the level of H(2)S in plasma of spontaneous hypertensive rats (SHR), and to study the role of H(2)S on the development of hypertension. METHODS: Twenty-four male SHR rats at the age of 4 weeks were randomly divided into SHR control group, SHR + NaHS (H(2)S donor) group and SHR + DL-propargylglycine (PPG) group, respectively. Another twenty-four male WKY rats were also divided into WKY control group, WKY + NaHS group and WKY + PPG group. SHR control and WKY control rats were injected with water. Rats of SHR + NaHS group and WKY + NaHS group were injected with NaHS, and rats of SHR + PPG group and WKY + PPG group were injected with PPG every day. Five weeks later, the blood pressure and the left-to-whole heart weight ratio were determined. The producing rate of H(2)S in aorta and the H(2)S level in plasma were also detected. RESULTS: The producing rate of H(2)S in aorta and the plasma level of H(2)S in SHR groups were all less than those of the corresponding WKY groups, however, the differences between SHR + PPG group and WKY + PPG group were not significant (P > 0.05). The producing rate of H(2)S and the plasma level of H(2)S in SHR + PPG group were similar to those of SHR control group. The producing rate of H(2)S and the plasma level of H(2)S in SHR + NaHS group were higher than those of SHR control. Both the producing rate and the plasma level of H(2)S in WKY + PPG group were less than those of WKY control. The producing rate of H(2)S in aorta of WKY + NaHS group was higher than that of WKY controls, while the plasma level of H(2)S in WKY + NaHS group was not different from that of WKY controls significantly. The blood pressure of SHR groups increased compared with that of WKY groups (P < 0.05). The blood pressure of SHR + PPG group was similar to that of SHR controls, while the blood pressure of SHR + NaHS reduced significantly compared with that of SHR controls. The blood pressure of WKY + PPG group was higher than that of WKY controls while the blood pressure of WKY + NaHS was similar to that of WKY controsl. CONCLUSIONS: H(2)S plays an important role in maintaining normal pressure and the reduced production of endogenous H(2)S is an essential factor in the development of spontaneous hypertension. Exogenous H(2)S provides a new way for interfering with the progression of hypertension.

Animals↗

PubMed2003

AI-guided parameter optimization in inverse treatment planning.

An artificial intelligence (AI)-guided inverse planning system was developed to optimize the combination of parameters in the objective function for intensity-modulated radiation therapy (IMRT). In this system, the empirical knowledge of inverse planning was formulated with fuzzy if-then rules, which then guide the parameter modification based on the on-line calculated dose. Three kinds of parameters (weighting factor, dose specification, and dose prescription) were automatically modified using the fuzzy inference system (FIS). The performance of the AI-guided inverse planning system (AIGIPS) was examined using the simulated and clinical examples. Preliminary results indicate that the expected dose distribution was automatically achieved using the AI-guided inverse planning system, with the complicated compromising between different parameters accomplished by the fuzzy inference technique. The AIGIPS provides a highly promising method to replace the current trial-and-error approach.

Algorithms↗

PubMed2003

Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy.

It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance and results in a low sensitivity of human cancer cells to therapeutic agents. A novel strategy to overcome the resistance is to target the apoptotic pathway directly. To identify molecular targets in the apoptotic pathway that are differentially regulated in cancer and normal cells, we have examined the levels of apoptotic effectors and inhibitors in human tumor and normal cell lines as well as in cancer and normal tissues. These include three pancreatic cancer lines (BXPC-3, MIA PaCa-2, and Panc-1), four breast cancer cell lines (MDA-MB-231, MDA-MB-435, MDA-MB-361, and MCF-7), and colon carcinoma line (SW620). Additionally, breast carcinoma tissue specimens were examined. Compared with normal human fibroblast and mammary epithelial cell lines, we detected high basal levels of caspase-3 and caspase-8 activities and active caspase-3 fragments in the tumor cell lines and cancer tissues in the absence of apoptotic stimuli. Furthermore, the tumor cells expressed high levels of survivin and XIAP, two members of the inhibitor of apoptosis (IAP) protein family. When the activity of these IAPs was blocked by expression of dominant-negative mutant survivin (survivinT34A) and XIAP-associated factor 1, respectively, apoptosis was induced in tumor but not normal cell lines. Moreover, down-regulation of both survivin and XIAP significantly enhanced tumor-cell apoptosis as compared with inhibition of either survivin or XIAP alone. These results suggest that up-regulated IAP expression counteracts the high basal caspase-3 activity observed in these tumor cells and that apoptosis in tumor cells but not normal cells can be induced by blocking IAP activity. Therefore, IAPs are important molecular targets for the development of cancer-specific therapeutic approaches.

Adaptor Proteins, Signal Transducing↗

PubMed2003

[Endogenous H2S is involved in the development of spontaneous hypertension].

Hydrogen sulfide (H2S) is recently found to be a new gaseous messenger playing an important role in many physiological and pathophysiological processes. The aim of this study was to explore the changes in endogenous H2S pathway and examine the effects of H2S on the development of spontaneous hypertensive rats (SHR). A controlled study on SHR and WKY rats at the age of 4 weeks showed that after 5 weeks of experiment, the blood pressure of SHR was markedly increased as compared with WKY rats (183.57 +/- 11.80 mm Hg vs 107.5 +/- 22.68 mm Hg, P < 0.05) and the ratio of left heart weight to whole heart weight of SHR was also increased as compared with WKY rats (0.85 +/- 0.02 vs 0.83 +/- 0.02, P < 0.05). While, the aortic H2S producing rate and H2S plasma level were decreased in SHR compared with WKY rats (15.63 +/- 2.89 nmol.min-1.g-1 vs 25.31 +/- 5.99 nmol.min-1.g-1, 20.35 +/- 9.20 mumol.L-1 vs 48.40 +/- 13.36 mumol.L-1, P < 0.05). NaHS, however, attenuated the high blood pressure and the ratio of left heart weight to whole heart weight of SHR (158.13 +/- 12.52 mm Hg vs 183.57 +/- 11.80 mm Hg and 0.83 +/- 0.03 vs 0.85 +/- 0.02), respectively. The above findings suggested that the reduced production of endogenous H2S was important in the development of spontaneous hypertension. The authors also observed that 5 weeks after the experiment the relaxing rate of aortic rings in response to acetylcholine in SHR was higher than that of WKY rats and NaHS enhanced the relaxing-response of aortic rings to acetylcholine in SHR significantly(P < 0.05). The aortic relaxing activities in both SHR and WKY rats displayed a dose-dependent response to different doses of NaHS. In conclusion, the reduced production of endogenous H2S in aorta is involved in the pathogenesis of spontaneous hypertension and is of great biological importance in modulating vasorelaxation.

Animals↗

PubMed2003

GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo.

With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTK(SR39)) fusion gene and the hNIS gene was developed. Ad5-yCD/mutTK(SR39)rep-hNIS and a replication-defective hNIS adenovirus (rAd-CMV-FLhNIS) were injected into contralateral lobes of the dog prostate and hNIS activity was monitored in live animals following administration of Na(99m)TcO(4) using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, (99m)TcO(4)(-) uptake was readily detected in the prostate using viral dose levels (10(10) to 10(12) viral particles) that have been safely administered to humans. Due to its rapid clearance and short physical half-life (6 h), it was possible to obtain daily measurements of (99m)TcO(4)(-) uptake in vivo, allowing for dynamic monitoring of reporter gene expression within the prostate as well as biodistribution throughout the body. High-resolution autoradiography of prostate sections coupled with 3D reconstruction of gene expression demonstrated that the magnitude and volume of gene expression could be quantified with submillimeter resolution. Implementation of the GENIS (gene expression of Na/I symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.

Adenoviridae↗

PubMed2003

Prognostic assessment of gastrointestinal stromal tumor.

The term "gastrointestinal stromal tumor" (GIST) has been applied to a collection of distinctive mesenchymal tumors occurring within the human gastrointestinal tract. As new drug therapy becomes available, data regarding the natural history of these unusual tumors are necessary to provide selection factors for treatment. Ninety-eight patients had light microscopy compatible with GIST at a single institution from 1989 to 2000. After immunostaining with c-kit and histopathologic review, 69 were judged to be GIST. All prognostic indicators were determined for gastric GIST, intestinal GIST, and all locations combined. The location of the GIST did not have a significant impact on survival. Clinically, tumor size, peritoneal cancer index, and completeness of cytoreduction had a significant impact on prognosis for GIST at all locations. Pathologically, cytologic atypia, necrosis, invasion and number of mitoses were significant prognostic indicators for GIST. Criteria to separate three pathologic groups of GIST according to the tumor size and the mitotic count were useful to evaluate the tumor behavior; in the borderline pathologic group invasion and cytologic atypia were statistically significant prognostic criteria. The cell phenotypes, as determined by immunostains, correlated with the prognosis of gastric GIST but not intestinal GIST. A correlation between the immunostain Ki-67 but not CD-34 or desmin and the prognosis was observed. It is possible to select clinical and pathologic parameters of GIST that impact on prognosis. Invasion and necrosis help to determine the prognosis with borderline tumors. The immunostain Ki-67 correlated with the prognosis and may be helpful to assess prognosis when dealing with small biopsy specimens.

Adult↗