bluuebunny/crossref_metadata_2025 huggingface dataset:
Antinociception of Heterotopic Electro-Acupuncture Mediated by the Dorsolateral Funiculus
Authors: Lee Seung Jae , Lyu Yeoung Su , Kang Hyung Won , Sohn In Churl , Koo Sungtae , Kim Min Sun , Park Byung Rim , Song Jeong Hoon , Kim Jae Hyo
Published: April 2007

We investigated the inhibitory pathways that mediate the antinociceptive effects of heterotopic electro-acupuncture (EA) on formalin injection-induced pain in rats. EA (2 ms, 10 Hz, 3 mA) was delivered to heterotopic acupoints HT7 and PC7 for 30 min; this was followed immediately by subcutaneous injection of formalin into the left hind paw of rats. Naltrexone (10 mg/kg, i.p.), an opioid receptor antagonist, was administered to evaluate the involvement of endogenous opioids. The dorsolateral funiculus (DLF), which is a descending pathway that inhibits pain, was transected at the ipsilateral T10–11 level of the thoracic spinal cord. EA inhibited behavioral responses to formalin injection-induced pain and prevented the pain-induced increase in cFos expression in the lumbar spinal cord. Pretreatment with naltrexone did not inhibit the antinociceptive effects of EA on formalin injection-induced pain. Transection of the DLF ipsilateral to the acupuncture site eliminated the antinociceptive effects of EA. These results suggest that the antinociceptive effects of heterotopic EA are mediated by the DLF and not by endogenous opioids.
Methanol Extract ofSorbus CommixtaCortex Prevents Vascular Inflammation in Rats with a High Fructose-Induced Metabolic Syndrome
Authors: Kang Dae Gill , Sohn Eun Jin , Lee An Sook , Kim Jin Sook , Lee Dae Ho , Lee Ho Sub
Published: April 2007

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.
The Water Extract of Adlay Seed (Coix lachrymajobi var. mayuen) Exhibits Anti-Obesity Effects Through Neuroendocrine Modulation
Authors: Kim Sung Ok , Yun Su-Jin , Lee Eunjoo H.
Published: April 2007

To find out whether the immunohistochemical expression of neuropeptid Y (NPY) and leptin receptor (LR) in the rat hypothalamus is influenced by adlay seed water extract (adlay), obesity in rats was induced by high fat diet (HFD) for 8 weeks; these rats were injected with 50 mg/100 g body weight adlay daily for 4 weeks. The results showed that the optical density of NPY immunoreactivity in paraventricular nucleus of rats increased approximately by 3.4 fold in HFD group compared to the normal diet group. Conversely, that of HFD + adlay group was about 2.6 fold lower than HFD group. The pattern of LR expression was similar to that of NPY. Both of NPY and LR mRNA levels, determined by real time PCR, in HFD + adlay group were decreased compared to those of HFD group, but there were no significant changes in the level of LR. These results suggest that adlay may regulate neuroendocrine activity in the brain. Accordingly, administration of adlay may be considered for therapies targeting obesity.
Effects of Tribuli Saponins on Ventricular Remodeling after Myocardial Infarction in Hyperlipidemic Rats
Authors: Guo Yan , Shi Da-Zhuo , Yin Hui-Jun , Chen Ke-Ji
Published: April 2007

This experiment was designed to determine whether Tribuli saponins (TS) relieve left ventricular remodeling (VR) after myocardial infarction (MI) in a murine hyperlipemia (HL) model. MI and HL models were induced and high and low doses of TS and simvastatin were administrated to the rats. Four weeks later, echocardiographic observation was performed and the left and right ventricular weight index (LVWI, RVWI) was calculated. Echocardiographic results showed that both high dose of TS and simvastatin had a beneficial effect on increasing fractional shortening (FS) and ejection fraction (EF), reducing left ventricular end diastolic volume (LVEDV), systolic volume (LVESV), left ventricular dimension end diastole (LVDd) and systole (LVDs), and decreasing LVWI, as compared to those in the HL-MI model group ( p < 0.05, 0.01). Both medicines had little impact on thickness of the anterior and posterior wall. No significant difference was observed between each treatment group ( p > 0.05). In conclusion, TS not only lowered serum lipidemia, but also relieved left ventricular remodeling, and improved cardiac function in the early stage after MI.
In Vivo and In Vitro Anti-inflammatory Activities of Neoandrographolide
Authors: Liu Jun , Wang Zheng-Tao , Ji Li-Li
Published: April 2007

Neoandrographolide, one of the principal diterpene lactones, isolated from a medicinal herb Andrographis paniculata Nees, was tested in vivo and in vitro for its anti-inflammatory activities and mechanism. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100–150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. In vitro studies were performed using the macrophage cell line RAW264.7 to study the effect of neoandrographolide on suppressing phorbol-12-myristate-13-acetate (PMA)-stimulated respiratory bursts and lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). Respiratory bursts were quantified by chemiluminescence (CL) measurements.Results showed that neoandrographolide suppressed PMA-stimulated respiratory bursts dose-dependently from 30 μM to 150 μM. Neoandrographolide also inhibited NO and TNF-α production in LPS-induced macrophages, contributing to the anti-inflammatory activity of A. paniculata. These results indicate that neoandrographolide possesses significant anti-inflammatory effects, which implies that it would be one of the major contributing components to participate in the anti-inflammatory effect of A. paniculata. and a potential candidate for further clinical trial.
TransgenicPanax ginsengInhibits the Production of TNF-α, IL-6, and IL-8 as well as COX-2 Expression in Human Mast Cells
Authors: Kim Su-Jin , Jeong Hyun-Ja , Yi Byoung-Jae , Kang Tae-Hee , An Nyeon-Hyung , Lee Eun-Hyub , Yang Deok-Chun , Kim Hyung-Min , Hong Seung-Heon , Um Jae-Young
Published: April 2007

The most well-known medicinal plant, Panax ginseng (P. ginseng), contains various phytosterols and bioactive triterpene saponins (ginsenosides). Squalene synthase is a key regulatory enzyme for triterpene biosynthesis and overexpression of the squalene synthase confers the hyper-production of triterpene saponins to form transgenic ginseng. In this study, we have investigated whether and how transgenic P. ginseng modulates an inflammatory reaction in a stimulated human mast cell line, HMC-1. It was found that transgenic P. ginseng inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and the expression of cyclooxygenase-2 in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. Additionally, we have shown that transgenic P. ginseng suppressed the intracellular calcium level induced by PMACI. These results provide new insights into the pharmacological actions of transgenic P. ginseng as a potential molecule for use in therapy in mast cell-mediated inflammatory diseases.
Compositions and Biological Activities of Essential Oils of Kadsura longepedunculata and Schisandra sphenanthera
Authors: Song Lei , Ding Jie-Ying , Tang Cui , Yin Chun-Hua
Published: April 2007

The chemical compositions, antimicrobial activities, antioxidant activities and cytotoxicities of the essential oils isolated from the root of Kadsura longepedunculata Finet et Gagnep (KLREO) and the fruit of Schisandra sphenanthera Rehd. et Wills. (SSFEO) were investigated.The analyses of gas chromatography-mass spectrometry (GC-MS) showed that cadinane type compounds and their derivatives were rich in both oils (54.2% and 39.7%, respectively) and δ-cadinene was the major component of both oils (13.8% and 25.6%, respectively). The antimicrobial activities of both oils were evaluated against five microorganisms with the disc diffusion and the broth micro-dilution method. Results showed that Gram-positive bacteria were more sensitive to both oils than Gram-negative bacteria and the yeast. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the oil of KLREO were lower than those of SSFEO, indicating that the former possessed slightly stronger antibacterial capability than the latter. The reducing power and lipid peroxidation assays were employed to study the potential antioxidant activities of both oils. Both oils remarkably decreased the content of malondialdehyde (MDA) in rat liver homogenate in a dose dependent manner. The antioxidant activities of KLREO appeared to be more potent than that of SSFEO. The oils of KLREO and SSFEO exhibited concentration-dependent cytotoxicities and were proved to be toxic to HepG2 cells with IC50 of 147 and 189 μg/ml, respectively.
QUANTUM PHASE TRANSITION IN BOSE–EINSTEIN CONDENSATES WITH CONTACT INTERACTION
Authors: PAN FENG , DRAAYER J. P.
Published: April 2007

Entanglement and occupation probabilities along the yrast line in the interacting Bose–Einstein condensates with contact interaction in two dimension is studied for the angular momentum quantum number L ≤ n with the help of a simple improved Mathematica package. Results of the entanglement along the yrast line up to L = 6 and occupation probabilities for the yrast states up to L = 5 are calculated, which show that the system undergoes a quantum phase transition for all the yrast states, of which the total number of bosons serves as the control parameter. The critical point is near n = L + 1.
(2+1)-DIMENSIONAL TD HIERARCHY AND ITS INTEGRABLE COUPLINGS
Authors: LI ZHU , DONG HUAN-HE
Published: April 2007

Under the frame of the (2 + 1)-dimensional zero curvature equation and Tu model, the (2 + 1)-dimensional TD hierarchy is obtained. Again, by using the expanding loop algebra, the integrable coupling system of the above hierarchy is given.
SHOT NOISE FOR ENTANGLED ELECTRONS WITH BERRY PHASE
Authors: ZHAO HUI , ZHAO XUEAN , LI YOU-QUAN
Published: April 2007

We study shot noise for entangled electrons in a 4-lead beam-splitter with one incoming lead driven by adiabatically rotating magnetic fields. We propose a setup of an adiabatically rotating magnetic field which is appropriate for an electron beam to transport through. Using the scattering matrix approach, we find that shot noise for the singlet and that for the entangled triplet oscillates between bunching and antibunching due to the influence of the Berry phase. It provides us with a new approach for testing the Berry phase in electron transport on the basis of entanglement.
Spectral reflectance: preliminary data on a new technique with potential for non-sulphide base metal exploration
Authors: McConachy Timothy F. , Yang Kai , Boni Maria , Evans Noreen J.
Published: April 2007

The growing economic importance of non-sulphide Zn and Pb deposits, and the relative subtlety of their surface expression, has led us to study the potential application of spectral reflectance of non-sulphide minerals as an exploration tool. A unique database of spectral reflectance properties for over 200 non-sulphide Pb and Zn mineral specimens was compiled and minerals from several groups were found to have potential exploration application. Well-developed absorption features in the visible- to near-infrared to short-wave infrared region characterize the Pb and Zn arsenates, carbonates, phosphates and sulphates, whereas the oxides have poor spectral responses in this wavelength region and the silicate signatures are highly variable. In particular, tarbuttite (Zn phosphate) was found to have a distinct spectral reflectance signature. Tarbuttite is an important economic constituent in the Skorpion Zn deposit in Namibia, and its spectral characteristics could be applied either to regional exploration programmes or as a complement to down-hole spectrometric nuclear logging for grade and quality control. These first encouraging results point to the need for spectral reflectance studies of similar secondary minerals in order to further develop this exploration tool and enhance our understanding of supergene mineralization genesis.
Olfactory epithelia exhibit progressive functional and morphological defects in CF mice
Authors: Grubb Barbara R. , Rogers Troy D. , Kulaga Heather M. , Burns Kimberlie A. , Wonsetler Robert L. , Reed Randall R. , Ostrowski Lawrence E.
Published: April 2007

In normal nasal epithelium, the olfactory receptor neurons (ORNs) are continuously replaced through the differentiation of progenitor cells. The olfactory epithelium (OE) of the cystic fibrosis (CF) mouse appears normal at birth, yet by 6 mo of age, a marked dysmorphology of sustentacular cells and a dramatic reduction in olfactory receptor neurons are evident. Electroolfactograms revealed that the odor-evoked response in 30-day-old CF mice was reduced ∼45%; in older CF mice, a ∼70% reduction was observed compared with the wild type (WT) response. Consistent with studies of CF airway epithelia, Ussing chamber studies of OE isolated from CF mice showed a lack of forskolin-stimulated Cl− secretion and an ∼12-fold increase in amiloride-sensitive sodium absorption compared with WT mice. We hypothesize that the marked hyperabsorption of Na+, most likely by olfactory sustentacular cells, leads to desiccation of the surface layer in which the sensory cilia reside, followed by degeneration of the ORNs. The CF mouse thus provides a novel model to examine the mechanisms of disease-associated loss of olfactory function.
Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress
Authors: Sautin Yuri Y. , Nakagawa Takahiko , Zharikov Sergey , Johnson Richard J.
Published: April 2007

Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.
Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs
Authors: O'Brien E. A. , Barnes V. , Zhao L. , McKnight R. A. , Yu X. , Callaway C. W. , Wang L. , Sun J. C. , Dahl M. J. , Wint A. , Wang Z. , McIntyre T. M. , Albertine K. H. , Lane R. H.
Published: April 2007

Intrauterine growth restriction (IUGR) increases the incidence of chronic lung disease (CLD). The molecular mechanisms responsible for IUGR-induced acute lung injury that predispose the IUGR infant to CLD are unknown. p53, a transcription factor, plays a pivotal role in determining cellular response to stress by affecting apoptosis, cell cycle regulation, and angiogenesis, processes required for thinning of lung mesenchyme. Because thickened lung mesenchyme is characteristic of CLD, we hypothesized that IUGR-induced changes in lung growth are associated with alterations in p53 expression and/or modification. We induced IUGR through bilateral uterine artery ligation of pregnant rats. Uteroplacental insufficiency significantly decreased serine-15-phosphorylated (serine-15P) p53, an active form of p53, in IUGR rat lung. Moreover, we found that decreased phosphorylation of lung p53 serine-15 localized to thickened distal air space mesenchyme. We also found that IUGR significantly decreased mRNA for targets downstream of p53, specifically, proapoptotic Bax and Apaf, as well as Gadd45, involved in growth arrest, and Tsp-1, involved in angiogenesis. Furthermore, we found that IUGR significantly increased mRNA for Bcl-2, an antiapoptotic gene downregulated by p53. We conclude that in IUGR rats, uteroplacental insufficiency induces decreased lung mesenchymal p53 serine-15P in association with distal lung mesenchymal thickening. We speculate that decreased p53 serine-15P in IUGR rat lungs alters lung phenotype, making the IUGR lung more susceptible to subsequent injury.
Sex differences in monocyte expression of IL-6: role of autonomic mechanisms
Authors: O'Connor Mary-Frances , Motivala Sarosh J. , Valladares Edwin M. , Olmstead Richard , Irwin Michael R.
Published: April 2007

Sex differences in the prevalence of inflammatory disorders exist, perhaps due to sex differences in cellular mechanisms that contribute to proinflammatory cytokine activity. This study analyzed sex differences of monocyte intracellular expression of IL-6 and its associations with reproductive hormones and autonomic mechanisms in 14 matched pairs of men and women ( n = 28). Monocyte intracellular IL-6 production was repeatedly assessed over two circadian periods. Sympathetic balance was estimated by heart rate variability and the ratio of power in the low-frequency (LF) to high-frequency (HF); vagal tone was indexed by the power of HF component. As compared to men, women showed greater monocyte expression of IL-6 across the circadian period. In addition, women showed lower sympathetic balance (LF/HF ratio), and greater levels of vagal tone (HF power). In women, but not men, sympathovagal balance was negatively associated with monocyte IL-6 expression, whereas vagal tone was positively associated with production of this cytokine. Levels of reproductive hormones were not related to monocyte IL-6 expression. The marked increase in monocyte expression of interleukin-6 in women has implications for understanding sex differences in risk of inflammatory disorders. Additionally, these data suggest that sex differences in sympathovagal balance or vagal tone may be a pathway to explain sex differences in IL-6 expression. Interventions that target autonomic mechanisms might constitute new strategies to constrain IL-6 production with impacts on inflammatory disease risk in women.
Effect of divalent heavy metals on epithelial Na+ channels in A6 cells
Authors: Yu Ling , Eaton Douglas C. , Helms My N.
Published: April 2007

To better understand how renal Na+ reabsorption is altered by heavy metal poisoning, we examined the effects of several divalent heavy metal ions (Zn2+, Ni2+, Cu2+, Pb2+, Cd2+, and Hg2+) on the activity of single epithelial Na+ channels (ENaC) in a renal epithelial cell line (A6). None of the cations changed the single-channel conductance. However, ENaC activity [measured as the number of channels ( N) × open probability ( Po)] was decreased by Cd2+ and Hg2+ and increased by Cu2+, Zn2+, and Ni2+ but was not changed by Pb2+. Of the cations that induced an increase in Na+ channel function, Zn2+ increased N, Ni2+ increased Po, and Cu2+ increased both. The cysteine modification reagent [2-(trimethylammonium)ethyl]methanethiosulfonate bromide also increased N, whereas diethylpyrocarbonate, which covalently modifies histidine residues, affected neither Po nor N. Cu2+ increased N and stimulated Po by reducing Na+ self-inhibition. Furthermore, we observed that ENaC activity is slightly voltage dependent and that the voltage dependence of ENaC is insensitive to extracellular Na+ concentration; however, apical application of Ni2+ or diethylpyrocarbonate reduced the channel voltage dependence. Thus the voltage sensor of Xenopus ENaC is different from that of typical voltage-gated channels, since voltage appears to be sensed by histidine residues in the extracellular loops of ENaC, rather than by charged amino acids in a transmembrane domain.
New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone
Authors: Bobadilla Norma A. , Gamba Gerardo
Published: April 2007

Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.
Cl−-dependent upregulation of human organic anion transporters: different effects on transport kinetics between hOAT1 and hOAT3
Authors: Ueo Harumasa , Motohashi Hideyuki , Katsura Toshiya , Inui Ken-ichi
Published: April 2007

Chloride ion has a stimulatory effect on the transport of organic anions across renal basolateral membranes. However, the exact mechanisms at molecular levels have been unclear as of yet. Human organic anion transporters hOAT1 and hOAT3 play important roles in renal basolateral membranes. In this study, the effects of Cl−on the activities of these transporters were evaluated by using HEK293 cells stably expressing hOAT1 or hOAT3 (HEK-hOAT1 or HEK-hOAT3). The uptake of p-[14C]aminohippurate by HEK-hOAT1 and [3H]estrone sulfate by HEK-hOAT3 was greater in the presence of Cl−than in the presence of SO42−or gluconate. Additionally, the uptake of various compounds by HEK-hOAT1 and HEK-hOAT3 was significantly higher in the Cl−-containing medium than the gluconate-containing medium, suggesting that the influences of Cl−are not dependent on substrate and that Cl−directly stimulates the functions of hOAT1 and hOAT3. The substitution of gluconate with Cl−did not change the Kmvalue for the uptake of p-[14C]aminohippurate by HEK-hOAT1 but caused an approximately threefold increase in the maximal uptake rate (Vmax) value. On the other hand, replacement of gluconate with Cl−decreased the Kmvalue for the uptake of [3H]estrone sulfate and cefotiam by HEK-hOAT3 to about one-third, while it did not change the Vmaxvalue. In summary, Cl−upregulates the activities of both hOAT1 and hOAT3, but its effects on transport kinetics differ between these transporters. It was suggested that Cl−participates in the trans-location process for hOAT1, and the substrate recognition process for hOAT3.
Substrate source utilization during moderate intensity exercise with glucose ingestion in Type 1 diabetic patients
Authors: Robitaille M. , Dubé M.-C. , Weisnagel S. J. , Prud'homme D. , Massicotte D. , Péronnet F. , Lavoie C.
Published: April 2007

Substrate oxidation and the respective contributions of exogenous glucose, glucose released from the liver, and muscle glycogen oxidation were measured by indirect respiratory calorimetry combined with tracer technique in eight control subjects and eight diabetic patients (5 men and 3 women in both groups) of similar age, height, body mass, and maximal oxygen uptake, over a 60-min exercise period on cycle ergometer at 50.8% (SD 4.0) maximal oxygen uptake [131.0 W (SD 38.2)]. The subjects and patients ingested a breakfast (containing ∼80 g of carbohydrates) 3 h before and 30 g of glucose (labeled with 13C) 15 min before the beginning of exercise. The diabetic patients also received their usual insulin dose [Humalog = 9.1 U (SD 0.9); Humulin N = 13.9 U (SD 4.4)] immediately before the breakfast. Over the last 30 min of exercise, the oxidation of carbohydrate [1.32 g/min (SD 0.48) and 1.42 g/min (SD 0.63)] and fat [0.33 g/min (SD 0.10) and 0.30 g/min (SD 0.10)] and their contribution to the energy yield were not significantly different in the control subjects and diabetic patients. Exogenous glucose oxidation was also not significantly different in the control subjects and diabetic patients [6.3 g/30 min (SD 1.3) and 5.2 g/30 min (SD 1.6), respectively]. In contrast, the oxidation of plasma glucose and oxidation of glucose released from the liver were significantly lower in the diabetic patients than in control subjects [14.5 g/30 min (SD 4.3) and 9.3 g/30 min (SD 2.8) vs. 27.9 g/30 min (SD 13.3) and 21.6 g/30 min (SD 12.8), respectively], whereas that of muscle glycogen was significantly higher [28.1 g/30 min (SD 15.5) vs. 11.6 g/30 min (SD 8.1)]. These data indicate that, compared with control subjects, in diabetic patients fed glucose before exercise, substrate oxidation and exogenous glucose oxidation overall are similar but plasma glucose oxidation is lower; this is associated with a compensatory higher utilization of muscle glycogen.
Estimates of the Location of L-type Ca2+ Channels in Motoneurons of Different Sizes: A Computational Study
Authors: Grande Giovanbattista , Bui Tuan V. , Rose P. Ken
Published: April 2007

In the presence of monoamines, L-type Ca2+ channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca2+ channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca2+ channels and test the hypothesis that the location of L-type Ca2+ channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca2+ channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca2+ channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.
Vestibular System May Provide Equivalent Motor Actions Regardless of the Number of Body Segments Involved in the Task
Authors: Raptis H. A. , Dannenbaum E. , Paquet N. , Feldman A. G.
Published: April 2007

The vestibulospinal system likely plays an essential role in motor equivalence—the ability to reach the desired motor goal despite intentional or imposed changes in the number of body segments involved in the task. To test this hypothesis, we compared the ability of healthy subjects and patients with unilateral vestibular lesions (surgical acoustic neuroma resection 0.6 to 6.7 yr before the study) to maintain either the same hand position or the same trajectory of within arm reach movements while flexing the trunk, in the absence of vision. In randomly selected trials, the trunk motion was prevented by an electromagnetic device. Healthy subjects were able to preserve the hand position or trajectory by modifying the elbow and shoulder joint rotations in a condition-dependent way, at a minimal latency of about 60 ms after the trunk movement onset. In contrast, six of seven patients showed deficits in the compensatory angular modifications at least in one of two tasks so that 30–100% of the trunk displacement was not compensated and thus influenced the hand position or trajectory. Results suggest that vestibular influences evoked by the head motion during trunk flexion play a major role in maintaining the consistency of arm motor actions in external space despite changes in the number of body segments involved. Our findings also suggest that despite long-term plasticity in the vestibular system and related neural structures, unilateral vestibular lesion may reduce the capacity of the nervous system to achieve motor equivalence.
Stochastic Resonance in the Motor System: Effects of Noise on the Monosynaptic Reflex Pathway of the Cat Spinal Cord
Authors: Martínez Lourdes , Pérez Toni , Mirasso Claudio R. , Manjarrez Elias
Published: April 2007

In sensory systems, the presence of a particular nonzero level of noise may significantly enhance the ability of an individual to detect weak sensory stimuli through a phenomenon known as stochastic resonance (SR). The aim of this study was to demonstrate if such phenomenon is also exhibited by the motor system; in particular, in the Ia-motoneuron synapse of the cat spinal cord. Monosynaptic reflexes elicited by periodic electrical stimulation to the medial gastrocnemius nerve were recorded in the L7 ventral root (or in single motoneurons) of decerebrated cats. Random stretches (mechanical noise) were applied to the lateral gastrocnemius plus soleus muscle by means of a closed-loop mechanical stimulator-transducer. In all cats, we observed the SR phenomenon. The amplitude of the monosynaptic reflexes (or number of action potentials recorded in the motoneurons) evoked by the weak electrical stimuli applied to the medial gastrocnemius nerve were an inverted U-like function of the mechanical noise applied to the lateral gastrocnemius plus soleus muscle. A significant maximum value in the amplitude of the monosynaptic responses was reached with a particular noise amplitude value. Numerical simulations on a model of the monosynaptic reflex pathway qualitatively reproduce this stochastic resonance behavior. We conclude that the monosynaptic reflex response elicited by Ia afferents is optimized by the noisy stretching of a synergistic muscle. Our study provides the first direct demonstration that the motor system, and not only the sensory systems, exhibits the SR phenomenon.
Inhibition of nuclear factor-κB augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation
Authors: Oida Yasuhisa , Gopalan Began , Miyahara Ryo , Branch Cynthia D. , Chiao Paul , Chada Sunil , Ramesh Rajagopal
Published: April 2007

Nuclear factor-κB (NF-κB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-κB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-κB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-κB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7–mediated NF-κB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative IκBα (dnIκBα) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7–treated H1299-dnIκBα compared with H1299-Neo cells. This Ad-mda7–mediated enhanced killing of H1299-dnIκBα cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnIκBα cells resulted in reduced Ad-mda7–mediated cell killing. In vivo, the treatment of H1299-dnIκBα s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7–treated H1299-Neo tumors. Molecular analysis of Ad-mda7–treated H1299-dnIκBα tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7–treated H1299-Neo tumors. Our findings thus showed that the NF-κB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-κB expression results in enhanced tumor cell killing. [Mol Cancer Ther 2007;6(4):1440–9]
Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met–expressing tumors
Authors: Francone Todd D. , Landmann Ron G. , Chen Chin-Tung , Sun Mark Y. , Kuntz Eleanor J. , Zeng Zhaoshi , Dematteo Ronald P. , Paty Philip B. , Weiser Martin R.
Published: April 2007

c-Met, a receptor tyrosine kinase responsible for cellular migration, invasion, and proliferation, is overexpressed in human cancers. Although ligand-independent c-Met activation has been described, the majority of tumors are ligand dependent and rely on binding of hepatocyte growth factor (HGF) for receptor activation. Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met. The goal of this study was to develop a xenograft model in which human HGF (hHGF) is produced in a controllable fashion in the mouse. Severe combined immunodeficient mice were treated with adenovirus encoding the hHGF transgene (Ad-hHGF) via tail vein injection, and transgene expression was determined by the presence of hHGF mRNA in mouse tissue and hHGF in serum. Ad-hHGF administration to severe combined immunodeficient mice resulted in hHGF production that was (a) dependent on quantity of virus delivered; (b) biologically active, resulting in liver hypertrophy; and (c) sustainable over 40 days. In this model, the ligand-dependent human tumor cell line SW1417 showed enhanced tumor growth, whereas the ligand-independent cell lines SW480 and GTL-16 showed no augmented tumor growth. This novel xenograft model is ideal for investigating c-Met/HGF–dependent human tumor progression and for evaluating c-Met targeted therapy. [Mol Cancer Ther 2007;6(4):1460–6]
Identification of a novel inhibitor of urokinase-type plasminogen activator
Authors: Zhu Ming , Gokhale Vijay M. , Szabo Lajos , Munoz Ruben M. , Baek Hyounggee , Bashyam Sridevi , Hurley Laurence H. , Von Hoff Daniel D. , Han Haiyong
Published: April 2007

Urokinase-type plasminogen activator (uPA), a highly restricted serine protease, plays an important role in the regulation of diverse physiologic and pathologic processes. Strong clinical and experimental evidence has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients. uPA has been considered as a promising molecular target for development of anticancer drugs. Here, we report the identification of several new uPA inhibitors using a high-throughput screen from a chemical library. From these uPA inhibitors, molecular modeling and docking studies identified 4-oxazolidinone as a novel lead pharmacophore. Optimization of the 4-oxazolidinone pharmacophore resulted in a series of structurally modified compounds with improved potency and selectivity. One of the 4-oxazolidinone analogues, UK122, showed the highest inhibition of uPA activity. The IC50 of UK122 in a cell-free indirect uPA assay is 0.2 μmol/L. This compound also showed no or little inhibition of other serine proteases such as thrombin, trypsin, plasmin, and the tissue-type plasminogen activator, indicating its high specificity against uPA. Moreover, UK122 showed little cytotoxicity against CFPAC-1 cells (IC50 >100 μmol/L) but significantly inhibited the migration and invasion of this pancreatic cancer cell line. Our data show that UK122 could potentially be developed as a new anticancer agent that prevents the invasion and metastasis of pancreatic cancer. [Mol Cancer Ther 2007;6(4):1348–56]
Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1
Authors: Baritaki Stavroula , Huerta-Yepez Sara , Sakai Toshiyuki , Spandidos Demetrios A. , Bonavida Benjamin
Published: April 2007

Several chemotherapeutic drugs in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) result in reversal of resistance to TRAIL-mediated apoptosis through up-regulation of DR5 expression. The promoter of DR5 has one putative binding site for the transcription repressor Yin Yang 1 (YY1), and thus, we hypothesized that the sensitizing drugs may inhibit YY1. We have found that treatment of tumor cells with various chemotherapeutic drugs inhibited nuclear factor-κB. We examined whether drugs also inhibit YY1 activity and whether YY1 inhibition correlates with up-regulation of DR5 expression and sensitization of cells to TRAIL-induced apoptosis. The TRAIL- and drug-resistant prostate carcinoma PC-3 cell line was treated with CDDP, VP-16, ADR, and vincristine. DR5 luciferase reporter constructs and small interfering RNA against YY1 were used to determine the role of YY1 in DR5 transcription. Pretreatment of PC-3 cells and other tumor cell lines with various chemotherapeutic drugs sensitized the cells to TRAIL-induced apoptosis concurrently with up-regulation of DR5 expression and inhibition of YY1 expression and its DNA-binding activity. The baseline luciferase activity in PC-3 cells transfected with the wild-type DR5 reporter was significantly augmented in cells transfected with DR5 constructs carrying deletions or mutation in the YY1-binding site. Treatment with drug enhanced DR5 wild-type luciferase activity, with no increase in cells transfected with the YY1-deleted or YY1-mutated constructs. Cells transfected with YY1 small interfering RNA showed up-regulation of DR5 expression and sensitization to TRAIL-mediated apoptosis. The findings provide evidence that drug-induced sensitization of tumor cells to TRAIL is mediated, in part, by inhibition of the transcription repressor YY1 and up-regulation of DR5 expression. Hence, YY1 may be a potential therapeutic target to reverse resistance to TRAIL-induced apoptosis. [Mol Cancer Ther 2007;6(4):1387–99]
Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer
Authors: Nahari Dorit , Satchi-Fainaro Ronit , Chen Ming , Mitchell Ian , Task Laurie B. , Liu Zijuan , Kihneman Jason , Carroll Allison B. , Terada Lance S. , Nwariaku Fiemu E.
Published: April 2007

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO′90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor–induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation. [Mol Cancer Ther 2007;6(4):1329–37]
The RET oncogene is a critical component of transcriptional programs associated with retinoic acid–induced differentiation in neuroblastoma
Authors: Oppenheimer Orit , Cheung Nai-Kong , Gerald William L.
Published: April 2007

Differentiation is a key feature in pathologic classification and prognosis of neuroblastic tumors, although the underlying molecular mechanisms are not well defined. To identify key differentiation-related molecules and pathways, we evaluated gene expression during retinoic acid (RA)–induced differentiation of seven neuroblastic tumor cell lines. Transcriptional response to RA was highly variable among cell lines despite the fact that six of seven showed similar morphologic changes. RA consistently altered expression of a small set of genes, some of which are known to play a role in neurogenesis and differentiation. Expression of genes that were regulated by RA was associated with important clinical subgroups of neuroblastic tumors and were differentially expressed by stroma-rich and stroma-poor subtypes. RET, a receptor tyrosine kinase involved with differentiation, was consistently up-regulated throughout the time course of RA treatment in the majority of neuroblastic tumor cell lines. Interference with RET activation abrogated RA-induced transcriptional programs and differentiation, suggesting a key role of RET in this process. The core set of RA-regulated genes includes critical molecular components of pathways necessary for neuroblastic tumor differentiation and have potential as therapeutic targets and molecular markers of response to differentiating agents. [Mol Cancer Ther 2007;6(4):1300–9]
Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib
Authors: Pyrko Peter , Kardosh Adel , Liu Yen-Ting , Soriano Nathaniel , Xiong Wenyong , Chow Robert H. , Uddin Jasim , Petasis Nicos A. , Mircheff Austin K. , Farley Robert A. , Louie Stan G. , Chen Thomas C. , Schönthal Axel H.
Published: April 2007

A drawback of extensive coxib use for antitumor purposes is the risk of life-threatening side effects that are thought to be a class effect and probably due to the resulting imbalance of eicosanoid levels. 2,5-Dimethyl-celecoxib (DMC) is a close structural analogue of the selective cyclooxygenase-2 inhibitor celecoxib that lacks cyclooxygenase-2–inhibitory function but that nonetheless is able to potently mimic the antitumor effects of celecoxib in vitro and in vivo. To further establish the potential usefulness of DMC as an anticancer agent, we compared DMC and various coxibs and nonsteroidal anti-inflammatory drugs with regard to their ability to stimulate the endoplasmic reticulum (ER) stress response (ESR) and subsequent apoptotic cell death. We show that DMC increases intracellular free calcium levels and potently triggers the ESR in various tumor cell lines, as indicated by transient inhibition of protein synthesis, activation of ER stress–associated proteins GRP78/BiP, CHOP/GADD153, and caspase-4, and subsequent tumor cell death. Small interfering RNA–mediated knockdown of the protective chaperone GRP78 further sensitizes tumor cells to killing by DMC, whereas inhibition of caspase-4 prevents drug-induced apoptosis. In comparison, celecoxib less potently replicates these effects of DMC, whereas none of the other tested coxibs (rofecoxib and valdecoxib) or traditional nonsteroidal anti-inflammatory drugs (flurbiprofen, indomethacin, and sulindac) trigger the ESR or cause apoptosis at comparable concentrations. The effects of DMC are not restricted to in vitro conditions, as this drug also generates ER stress in xenografted tumor cells in vivo, concomitant with increased apoptosis and reduced tumor growth. We propose that it might be worthwhile to further evaluate the potential of DMC as a non-coxib alternative to celecoxib for anticancer purposes. [Mol Cancer Ther 2007;6(4):1262–75]
1α,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells
Authors: Ben-Shoshan Moshe , Amir Sharon , Dang Duyen T. , Dang Long H. , Weisman Yosef , Mabjeesh Nicola J.
Published: April 2007

In vitro and in vivo studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits angiogenesis in cancer. We now examined whether the antiangiogenic effects of 1,25(OH)2D3 are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)2D3 reduces the protein expression of both the regulated HIF-1α subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)2D3 also inhibited HIF-1 transcriptional activity (measured by reporter gene assay) as well as HIF-1 target genes, including VEGF, ET-1, and Glut-1. We also showed that 1,25(OH)2D3 inhibits cell proliferation under hypoxia. Using HIF-1α knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)2D3 is mediated through a HIF-dependent pathway. Because HIF-1 is a major positive contributor in human tumorigenesis and angiogenesis, we believe that its inhibition by 1,25(OH)2D3 strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy. [Mol Cancer Ther 2007;6(4):1433–9]