bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydronephrosis causes salt‐sensitive hypertension and impaired renal concentrating ability in mice
Authors: Carlström M. , Sällström J. , Skøtt O. , Larsson E. , Wåhlin N. , Persson A. E. G. 
Published: January 2007

AbstractAim:  Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt‐sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt‐sensitive hypertension.Methods:  PUUO was created in 3‐week‐old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated.Results:  All hydronephrotic animals developed salt‐sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes.Conclusion:  This study provides a model for PUUO in mice and demonstrates the presence of salt‐sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.
Characterization of GLUT4 and calpain expression in healthy human skeletal muscle during fasting and refeeding
Authors: Norton L. , Parr T. , Bardsley R. G. , Ye H. , Tsintzas K. 
Published: January 2007

AbstractAims:  Calpain‐10 and calpain‐3 and the diabetes ankyrin repeat protein (DARP) have all been linked to insulin resistance and type 2 diabetes. We set out to measure the expression of these genes in human skeletal muscle and relate them to functional measurements of insulin action during fasting (which induces insulin resistance) and refeeding (which reverses it).Methods:  Ten healthy male volunteers underwent 48 h of starvation followed by 24 h of high carbohydrate refeeding. On three occasions, before and after starvation and after refeeding, subjects underwent a 16 min insulin tolerance test to quantify insulin sensitivity. Muscle biopsies were obtained before and after fasting and after refeeding for the analysis of calpain‐10 and calpain‐3, GLUT4 and DARP expression by Western blotting and real‐time PCR.Results:  Fasting led to a marked reduction in whole body insulin sensitivity by approx. 45% (P < 0.01) and skeletal muscle GLUT4 gene expression by approx. 40% (P < 0.05). However, fasting had no effect on calpain‐10 and calpain‐3 mRNA or protein levels, or DARP mRNA expression. Refeeding only partly restored insulin sensitivity and GLUT4 gene expression to their pre‐fast values, but did not effect the expression of calpain‐10, calpain‐3 or DARP.Conclusions:  These findings demonstrate that in healthy non‐diabetic humans induction of insulin resistance by fasting and its reversal by refeeding with a high CHO diet is mirrored by changes in skeletal muscle GLUT4 but not calpain‐10 and calpain‐3 expression.
Dantrolene, like fatigue, has a length‐dependent effect on submaximal force–length relationships of rat gastrocnemius muscle
Authors: MacNaughton M. B. , Campbell J. J. , MacIntosh B. R. 
Published: January 2007

AbstractAim:  Fatigue is length‐dependent; relative active force depression is greater when measured at short lengths than at long lengths. Several unsatisfactory mechanisms have been proposed to explain this length dependence of fatigue, including: damaged myofilaments, stretch of ‘in‐series’ structures, impaired t‐tubule conduction and reduced intensity of activation. Dantrolene targets the ryanodine receptors, inhibiting stimulation‐induced release of Ca2+. The purpose of this study was to determine if the force depression caused by dantrolene treatment also has a length dependence.Methods:  Submaximal (single‐pulse, double‐pulse and 50 Hz stimulation) active force–length relationships were obtained from the medial gastrocnemius muscle of anaesthetized rats, before and after intravenous injection with dantrolene dissolved in propylene glycol.Results:  Dantrolene treatment was sufficient to reduce twitch amplitude by 25%. Similar to the consequences of repetitive stimulation, dantrolene treatment caused the same decrease in absolute active force across a broad range of test lengths, for twitch, double‐pulse and 50 Hz contractions. Considering that active force is smaller at short lengths than at long lengths, this similar absolute force decrease represents a greater relative decrease at short lengths. Clearly, there is a length‐dependent impact of attenuated Ca2+ release by dantrolene on relative active force.Conclusion:  This study demonstrates that there is a length dependence of force depression associated with decreased Ca2+ release due to dantrolene treatment; therefore, if fatigue is due to decreased Ca2+ release, then additional length‐dependent mechanisms are not required to explain the reported length dependence of force depression.
Distribution pattern of endangered bird species in China
Authors: LEI Fumin , ZHAO Hongfeng , YIN Zuohua 
Published: January 2007

AbstractIn this study, we determined six “hotspots” for avian biodiversity conservation in China. We analyzed the distribution patterns of 183 threatened bird species in China in conjunction with geographical data to produce a distribution map that shows the concentrations of threatened species. The six biodiversity hotspots are: the western Tianshan Mountains; the Qilian and Hengduan mountains; southern Anhui, southern Jiangsu, and the Zhejiang Hills; the Songliao Plain and the northern region of the North China Plain; the island of Taiwan; and the island of Hainan. Based on our analysis of a species–habitat matrix, species were determined to be distributed mainly in broadleaved forest, grassland and meadows, urban and agricultural areas, wetlands, and bush. Most species were commonly found to have a range of three to five different habitat types. Apart from the six biodiversity hotspots, six ecological clusters were determined. Protection strategies indicating different levels of habitat priority among the biodiversity hotspots were also recommended.
Hygromycin B Inhibition of Protein Synthesis and Ribosome Biogenesis in
Escherichia coli
Authors: McGaha Susan M. , Champney W. Scott 
Published: January 2007

ABSTRACT

The aminoglycoside antibiotic hygromycin B was examined in
Escherichia coli
cells for inhibitory effects on translation and ribosomal-subunit formation. Pulse-chase labeling experiments were performed, which verified lower rates of ribosomal-subunit synthesis in drug-treated cells. Hygromycin B exhibited a concentration-dependent inhibitory effect on viable-cell numbers, growth rate, protein synthesis, and 30S and 50S subunit formation. Unlike other aminoglycosides, hygromycin B was a more effective inhibitor of translation than of ribosomal-subunit formation in
E. coli
. Examination of total RNA from treated cells showed an increase in RNA corresponding to a precursor to the 16S rRNA, while mature 16S rRNA decreased. Northern hybridization to rRNA in cells treated with hygromycin B showed that RNase II- and RNase III-deficient strains of
E. coli
accumulated 16S rRNA fragments upon treatment with the drug. The results indicate that hygromycin B targets protein synthesis and 30S ribosomal-subunit assembly.
The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80
Authors: Kessel David , Reiners John J. , Hazeldine Stuart T. , Polin Lisa , Horwitz Jerome P. 
Published: January 2007

AbstractThe phenoxypropionic acid derivative 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) and an analogue termed 2-{4-[(7-bromo-2-quinalinyl)oxy]phenoxy}propionic acid (SH80) can eradicate malignant cell types resistant to many common antitumor agents. Colony formation assays indicated that a 24 h exposure of L1210 cells to XK469 or SH80 inhibited clonogenic growth with CI90 values of 10 and 13 μmol/L, respectively. This effect was associated with G2-M arrest and the absence of any detectable markers of apoptosis (i.e., plasma membrane blebbing, procaspase 3 activation, loss of mitochondrial membrane potential, and formation of condensed chromatin). Drug-treated cells increased in size and eventually exhibited the characteristics of autophagy (i.e., appearance of autophagosomes and conversion of microtubule-associated protein light chain 3-I to 3-II). The absence of apoptosis was not related to an inhibition of the apoptotic program. Cultures treated with XK469 or SH80 readily underwent apoptosis upon exposure to the Bcl-2/Bcl-xL antagonist ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate. Continued incubation of drug-treated cells led to a reciprocal loss of large autophagic cells and the appearance of smaller cells that could not be stained with Höechst dye HO33342, had a chaotic morphology, were trypan blue–permeable, and lacked mitochondrial membrane potential. L1210 cells cotreated with the phosphatidylinositol-3-kinase inhibitor wortmannin, or having reduced Atg7 protein content, underwent G2-M arrest, but not autophagy, following XK469 treatment. Hence, the therapeutic actions of XK469/SH80 with L1210 cultures reflect both the initiation of a cell cycle arrest as well as the initiation of autophagy. [Mol Cancer Ther 2007;6(1):370–9]
About a switch: how P-glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work
Authors: Sauna Zuben E. , Ambudkar Suresh V. 
Published: January 2007

Abstract
The efflux of drugs by the multidrug transporter P-glycoprotein (Pgp; ABCB1) is one of the principal means by which cancer cells evade chemotherapy and exhibit multidrug resistance. Mechanistic studies of Pgp-mediated transport, however, transcend the importance of this protein per se as they help us understand the transport pathway of the ATP-binding cassette proteins in general. The ATP-binding cassette proteins comprise one of the largest protein families, are central to cellular physiology, and constitute important drug targets. The functional unit of Pgp consists of two nucleotide-binding domains (NBD) and two transmembrane domains that are involved in the transport of drug substrates. Early studies postulated that conformational changes as a result of ATP hydrolysis were transmitted to the transmembrane domains bringing about drug transport. More recent structural and biochemical studies on the other hand suggested that ATP binds at the interface of the two NBDs and induces the formation of a closed dimer, and it has been hypothesized that this dimerization and subsequent ATP hydrolysis powers transport. Based on the mutational and biochemical work on Pgp and structural studies with isolated NBDs, we review proposed schemes for the catalytic cycle of ATP hydrolysis and the transport pathway. [Mol Cancer Ther 2007;6(1):13–23]
The role of spermidine/spermineN1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells
Authors: Allen Wendy L. , McLean Estelle G. , Boyer John , McCulla Andrea , Wilson Peter M. , Coyle Vicky , Longley Daniel B. , Casero Robert A. , Johnston Patrick G. 
Published: January 2007

AbstractPolyamines have been shown to play a role in the growth and survival of several solid tumors, including colorectal cancer. We identified the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) as being one of the most highly inducible genes in two DNA microarray screens to identify novel determinants of response to chemotherapeutic agents in colorectal cancer. SSAT was shown to be inducible in response to 5-fluorouracil (5-FU) or oxaliplatin in parental and drug-resistant HCT116 cell lines. It was also shown that SSAT mRNA was up-regulated in response to 5-FU or oxaliplatin in a panel of six colorectal cancer cell lines. The polyamine analogue N1,N11-diethylnorspermine (DENSpm) depletes polyamine pools and potently induces SSAT. We evaluated the effect of combining DENSpm with chemotherapeutic agents in HCT116 p53+/+ cells and in HCT116 drug-resistant daughter cell lines. Western blot analyses showed that SSAT protein expression was dramatically enhanced when DENSpm was combined with oxaliplatin or 5-FU in HCT116 p53+/+ cells. Using cell viability assays and flow cytometry, synergistic induction of cell death was observed following cotreatment of HCT116 p53+/+ cells with DENSpm and each chemotherapeutic agent. Of note, this combined therapy increased the chemosensitivity of cells rendered resistant to each of these chemotherapeutic agents. Small interfering RNA–mediated down-regulation of SSAT resulted in loss of synergy between DENSpm and these agents. These results show that SSAT plays an important role in regulating cell death following combined cytotoxic drug and DENSpm treatment. Furthermore, DENSpm sensitizes both sensitive and resistant cells to chemotherapeutic agents. Taken together, these results suggest that SSAT may be an important target for therapeutic intervention in colorectal cancer. [Mol Cancer Ther 2007;6(1):128–37]
Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells
Authors: Park Moon-Taek , Kang Young-Hee , Park In-Chul , Kim Chun-Ho , Lee Yun-Sil , Chung Hee Yong , Lee Su-Jae 
Published: January 2007

Abstract
Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As2O3) enhanced cell death of naturally As2O3-resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-l-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment–induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-l-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As2O3 induces synergistic apoptosis in As2O3-resistant leukemia cells through the p38 MAPK–mediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As2O3 treatment. [Mol Cancer Ther 2007;6(1):82–92]
Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts
Authors: Anai Satoshi , Goodison Steve , Shiverick Kathleen , Hirao Yoshihiko , Brown Bob D. , Rosser Charles J. 
Published: January 2007

Abstract
Expression of the proto-oncogene Bcl-2 is associated with tumor progression. Bcl-2's broad expression in tumors, coupled with its role in resistance to chemotherapy and radiation therapy–induced apoptosis, makes it a rational target for anticancer therapy. Antisense Bcl-2 oligodeoxynucleotide (ODN) reagents have been shown to be effective in reducing Bcl-2 expression in a number of systems. We investigated whether treating human prostate cancer cells with antisense Bcl-2 ODN (G3139, oblimersen sodium, Genasense) before irradiation would render them more susceptible to radiation effects. Two prostate cancer cell lines expressing Bcl-2 at different levels (PC-3-Bcl-2 and PC-3-Neo) were subjected to antisense Bcl-2 ODN, reverse control (CTL), or mock treatment. Antisense Bcl-2 ODN alone produced no cytotoxic effects and was associated with G1 cell cycle arrest. The combination of antisense Bcl-2 ODN with irradiation sensitized both cell lines to the killing effects of radiation. Both PC-3-Bcl-2 and PC-3-Neo xenografts in mice treated with the combination of antisense Bcl-2 ODN and irradiation were more than three times smaller by volume compared with xenografts in mice treated with reverse CTL alone, antisense Bcl-2 ODN alone, irradiation alone, or reverse CTL plus radiotherapy (P = 0.0001). Specifically, PC-3-Bcl-2 xenograft tumors treated with antisense Bcl-2 ODN and irradiation had increased rates of apoptosis and decreased rates of angiogenesis and proliferation. PC-3-Neo xenograft tumors had decreased proliferation only. This is the first study which shows that therapy directed at Bcl-2 affects tumor vasculature. Together, these findings warrant further study of this novel combination of Bcl-2 reduction and radiation therapy, as well as Bcl-2 reduction and angiogenic therapy. [Mol Cancer Ther 2007;6(1):101–11]
Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling
Authors: Mullen Peter , Cameron David A. , Hasmann Max , Smyth John F. , Langdon Simon P. 
Published: January 2007

Abstract
Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin β1 (HRGβ1) or transforming growth factor-α, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGβ1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-α−stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGβ1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGβ1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGβ1-enhanced phosphorylation of HER2 (Tyr877) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease. [Mol Cancer Ther 2007;6(1):93–100]
Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes
Authors: Yates Melinda S. , Tauchi Masafumi , Katsuoka Fumiki , Flanders Kathleen C. , Liby Karen T. , Honda Tadashi , Gribble Gordon W. , Johnson Delinda A. , Johnson Jeffrey A. , Burton Neal C. , Guilarte Tomás R. , Yamamoto Masayuki , Sporn Michael B. , Kensler Thomas W. 
Published: January 2007

AbstractSynthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 μmol/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs. [Mol Cancer Ther 2007;6(1):154–62]
Synergism between vitamin D and secreted protein acidic and rich in cysteine–induced apoptosis and growth inhibition results in increased susceptibility of therapy-resistant colorectal cancer cells to chemotherapy
Authors: Taghizadeh Farnaz , Tang Michelle J. , Tai Isabella T. 
Published: January 2007

Abstract
Patients with advanced colorectal cancer continue to have poor outcomes because of therapy-refractory disease. We previously showed that secreted protein acidic and rich in cysteine (SPARC) gene and protein could function as a chemotherapy sensitizer by enhancing tumor regression in response to radiation and chemotherapy in tumor xenograft models of chemotherapy-resistant tumors. This function of SPARC was gleamed from a microarray analysis that also revealed down-regulation of the vitamin D receptor (VDR) in therapy-refractory colorectal cancer cells. This study examines the potential synergistic effect of SPARC and vitamin D, which up-regulates VDR, in enhancing chemotherapy response in colorectal cancer. Using MIP101 colorectal cancer cell lines and SPARC-overexpressing MIP101 cells, we were able to show that, in the presence of SPARC, exposure to low doses of 1α,25-dihydroxyvitamin D3 significantly reduces cell viability, enhances chemotherapy-induced apoptosis, and inhibits the growth of colorectal cancer cells. Moreover, in tumor xenograft mouse models, up-regulation of VDR was seen in tumors that had the greatest regression following treatment that combined SPARC with chemotherapy. Therefore, our findings reveal a synergistic effect between SPARC and low doses of 1α,25-dihydroxyvitamin D3 that further augments the sensitivity of tumors to chemotherapy. This combination may prove to be a useful adjunct in the treatment of colorectal cancer, especially in those patients with therapy-refractory disease. [Mol Cancer Ther 2007;6(1):309–17]