SEARCH · Search PubMed

Results for “Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,027 records · Page 57Linked to original sources

PubMed2005

Inhibition of either phosphatidylinositol 3-kinase/Akt or the mitogen/extracellular-regulated kinase, MEK/ERK, signaling pathways suppress growth of breast cancer cell lines, but MEK/ERK signaling is critical for cell survival.

The phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are important integrators of growth and survival signals originating from extracellular stimuli. We assessed the importance of these signaling pathways in the growth and survival of 8 breast cell lines (MCF10A, an immortalized line; and 7 cancer cell lines). The cell lines expressed variable levels of both phosphorylated ERK and phosphorylated Akt, but these were unchanged by incubation in serum-free medium. Despite continued activity of these pathways, the cells arrested growth in the absence of serum demonstrating that additional pathways are required for growth. Incubation with the PI3K inhibitor LY294002 suppressed growth of all cell lines, but most remained viable for at least 7-14 days. This long-term survival may be attributable to recovery of phospho-Akt by 24-48 h despite the continued presence of active LY294002, suggesting that alternate pathways may be activating Akt. In contrast, incubation with the MEK inhibitor U0126 not only arrested growth, but also killed all the cell lines within 2-4 days in the absence of serum; the presence of serum only slighted extended viability, except in MCF10A and MDA-MB-468 cells, in which serum provided significantly greater protection. It is likely that these signaling pathways control the level of pro-and anti-apoptotic proteins, yet assessment of Bcl-2 and Bcl-X showed dramatic reduction in level only when large numbers of cells were dead suggesting this may be a consequence rather than cause of death. Overall, the results demonstrate that the MEK/ERK pathway represents the more critical pathway for cell survival of these breast cancer cell lines, and suggest this pathways represents the better target for cancer therapy.

Blotting, Western↗

PubMed1986

Susceptibility to atrial fibrillation and ventricular tachyarrhythmia in the Wolff-Parkinson-White syndrome: role of the accessory pathway.

Clinical and electrophysiologic characteristics associated with spontaneous and inducible atrial fibrillation and ventricular tachyarrhythmia were assessed in 20 consecutive patients with Wolff-Parkinson-White (WPW) syndrome undergoing surgical division (n = 12) or transcatheter electrical ablation (n = 8) of accessory pathways. Patients with spontaneous atrial fibrillation were characterized by the trend (not significant) of a shorter antegrade accessory pathway effective refractory period (256 +/- 26 vs 303 +/- 109 msec). However, patients with and without spontaneous atrial fibrillation did not differ with respect to prevalence of structural heart disease (3 of 11 vs 2 of 9), intra-atrial conduction time (34 +/- 10 vs 32 +/- 10 msec), or interatrial conduction time (86 +/- 21 vs 88 +/- 17 msec). Thus, atrial and accessory pathway electrophysiologic properties (per se) were not clear determinants of susceptibility to atrial fibrillation. Among the 20 patients, 10 to 35 beats of nonsustained ventricular tachycardia (seven patients) or ventricular fibrillation (three patients) were induced at electrophysiologic study with one to three programmed extrastimuli. Clinically, a ventricular arrhythmia (ventricular fibrillation during atrial fibrillation) had occurred in only one of these patients. The discordance of these observations was significant (p less than 0.01). Patients with and without inducible ventricular arrhythmias were not distinguished by clinical factors or by electrophysiologic properties of the accessory pathway or ventricles. Accessory pathway conduction was completely or partially eliminated by ablation procedures in 14 of 20 patients. During a mean follow-up of 27 months, atrial fibrillation recurred in two patients with failed ablation procedures and in one patient with left atrial enlargement (despite accessory pathway division) (p = 0.019 vs pre-ablation). Ventricular arrhythmias remained inducible in two patients in whom accessory pathway ablation failed (p = 0.01 vs initial study). However, spontaneous ventricular tachyarrhythmias did not occur during follow-up. We conclude that susceptibility to spontaneous or inducible atrial fibrillation and ventricular tachyarrhythmia in patients with WPW syndrome and no organic heart disease depends primarily on the existence of a functional accessory pathway. These susceptibilities are eliminated by interruption of accessory pathway conduction. Ventricular tachyarrhythmias remain infrequent spontaneous events in the WPW syndrome. Their more frequent induction at electrophysiologic study is not predictive of clinical occurrence.

Atrial Fibrillation↗

PubMed1995

Prospective study of retrograde coronary venography in patients with posteroseptal and left-sided accessory atrioventricular pathways.

The morphologic features of the coronary vein system was prospectively studied with retrograde venography in 117 patients with left-sided (78 patients) and posteroseptal accessory pathway (39). Findings were compared with accessory pathway localization. A mean of 3.3 +/- 1.5 venous branches draining into the coronary sinus or the great cardiac vein could be visualized. The morphologic condition was described and classified. Incidence, morphologic condition, and distribution did not differ between left-sided and posteroseptal accessory pathway. Venous abnormalities including ectasy, diverticulum, narrowing, angulation, and hypoplasia occurred in 22.2%. Diverticulum and narrowing were present in posteroseptal accessory pathway only and always related to the successful ablation site. In patients with left-sided accessory pathway, ectasy, angulation, and hypoplasia were found. Anomalies were less frequent (9% vs 43.6%, p < 0.001) and had no relation to accessory pathway localization. However, the successful ablation site was in 42.3% located < 5 mm to an angiographically visualized venous branch. In conclusion, posteroseptal accessory pathways are often related to coronary sinus abnormalities. In patients with a left-sided accessory pathway venous malformation is uncommon, whereas a close anatomic relation exists between accessory pathway localization and venous ventricular branches.

Adolescent↗

PubMed1980

Simultaneous anterograde fast-slow atrioventricular nodal pathway conduction after procainamide.

UNLABELLED: Three patients with paroxysmal supraventricular tachycardia underwent electrophysiologic studies that included His bundle recordings, incremental atrial and ventricular pacing and extrastimulation before and after intravenous infusion of 500 mg of procainamide. In all three patients the tachycardia was induced during atrial pacing or premature atrial stimulation, or both. Two of the three patients had discontinuous atrioventricular (A-V) nodal curves with induction of a slow-fast tachycardia during failure in anterograde fast pathway conduction and one patient had a smooth A-V nodal curve with induction of a slow-fast tachycardia at critical A-H interval delays. After procainamide: (1) in all three patients atrial pacing induced A-V nodal Wenckebach periodicity (cycle length 300 to 400 ms) resulting in simultaneous anterograde fast and slow pathway conduction (one atrial beat resulting in two QRS complexes) and retrograde fast pathway conduction initiating an echo response or a slow-fast tachycardia, or both; (2) in all three patients there was enhanced conduction and shortening of refractoriness of the anteriograde fast pathway and depressed conduction and lengthening of refractoriness of the retrograde fast pathway; and (3) in two patients there was inability to sustain tachycardia because of selective block within the retrograde fast pathway. IN CONCLUSION: (1) procainamide altered conduction and refractoriness of the anterograde fast and slow pathways so that simultaneous conduction could occur during atrial pacing, resulting in a double ventricular response and a slow-fast echo or tachycardia, or both; and (2) the differential effects of procainamide on anterograde fast and retrograde fast pathways suggests two functional A-V nodal fast pathways, oine for anterograde and the other for retrograde conduction.

Aged↗

PubMed1988

Effects of upright posture on atrioventricular nodal reentry and dual atrioventricular nodal pathways.

The electrophysiologic effects of upright posture (45 degrees upright tilt) were studied in 17 patients with dual atrioventricular (AV) nodal pathways, AV nodal reentry or both. Discontinuous AV nodal conduction curves were observed in 16 patients while supine, but in only 11 patients while upright. Fast pathway refractoriness was shortened: the anterograde fast pathway effective refractory period decreased from 360 +/- 22 to 275 +/- 14 ms (mean +/- standard error of the mean), the anterograde fast pathway block cycle length shortened from 448 +/- 28 to 348 +/- 20 ms and the retrograde fast pathway block cycle length shortened from 425 +/- 29 to 338 +/- 24 ms (all p less than 0.01). The anterograde slow pathway block cycle length shortened from 378 +/- 29 to 316 +/- 17 ms (p less than 0.05). AV nodal reentrant tachycardia was induced in 5 patients while supine (2 sustained, 3 nonsustained) and in 6 patients while upright (4 sustained, 2 nonsustained). Tachycardia cycle length shortened during upright posture, from 413 +/- 30 to 345 +/- 22 ms (p less than 0.01), primarily due to shortened anterograde slow pathway conduction time, from 322 +/- 23 to 268 +/- 20 ms (p less than 0.05). Upright posture thus enhances conduction in patients with dual AV nodal pathways, facilitating AV nodal reentry. Electrophysiologic testing in the upright position may yield additional clinical important information in patients with dual AV nodal pathways.

Atrioventricular Node↗

PubMed1993

Radiofrequency ablation in multiple accessory pathways and the physiologic implications.

The presence of multiple accessory pathways was noted in 24 of 210 consecutive patients (12 males and 12 females aged 15 to 77 years [mean +/- SD 43 +/- 16]) with the Wolff-Parkinson-White syndrome who underwent electrophysiologic study and radiofrequency ablation. Six had 3 and 18 had 2 accessory pathways. There were 25 manifest and 29 concealed accessory pathways. The location of the accessory pathways was in the left free wall in 22, the right free wall in 17, the left posterior portion of the ventricular septum in 8, the right posterior portion of the ventricular septum in 6, and the midseptum in 1. The success rate of accessory pathway ablation and the fluoroscopic time in these 24 patients with multiple accessory pathways were 89% and 78 +/- 66 minutes, respectively, whereas they were 98% (p < 0.01) and 36 +/- 37 minutes (p = 0.01) in the 186 patients with a single accessory pathway. The mean applications, the power level of the radiofrequency current and the application duration in these 24 patients were 21 +/- 22, 30 +/- 3 W, and 27 +/- 10 seconds, respectively. In the 186 patients with a single accessory pathway, they were 9 +/- 12 applications (p = 0.02), 30 +/- 4 W (p = NS) and 26 +/- 9 seconds (p = NS), respectively. Seventeen of the 24 patients had a follow-up electrophysiologic study 89 +/- 40 days after ablation, and 2 (12%) had resumption of a right and left accessory pathway conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Predictors of recurrent atrioventricular nodal reentry after selective slow pathway ablation.

Although radiofrequency catheter ablation of the slow atrioventricular (AV) nodal pathway is highly effective for the management of AV nodal reentrant tachycardia (AVNRT), this arrhythmia may recur in some patients after an ablation procedure that initially renders AVNRT noninducible. A retrospective study examined the factors that are associated with the recurrence of AVNRT after selective radiofrequency catheter ablation of the slow pathway. Patients were included in the study if they had initially inducible, typical slow-fast AVNRT that was noninducible at the end of the ablation session. Selective ablation of the slow pathway was performed using radiofrequency energy applied along the tricuspid annulus near the coronary sinus ostium. AVNRT recurred after initially successful slow pathway ablation in 10 of 136 patients (7.4%) over a mean follow-up period of 20.1 +/- 5.0 months; the time to recurrence ranged from 1 to 411 days. Despite the absence of inducible AVNRT, dual anterograde AV nodal conduction properties persisted after slow pathway ablation in 10 patients. AVNRT recurred in 4 of 10 patients who had evidence of residual slow pathway conduction compared with only 6 of 126 who had no residual slow pathway conduction (p = 0.003). All patients with persistent slow pathway conduction and recurrent AVNRT also had residual AV nodal echo beats. AVNRT recurred in 3 of 6 patients without accelerated junctional tachycardia during radiofrequency application compared with only 7 of 109 with accelerated junctional tachycardia (p = 0.003). Thus, AVNRT infrequently recurs after successful selective radiofrequency ablation of the slow pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrioventricular Node↗

PubMed1995

Composite control of cell function: metabolic pathways behaving as single control units.

This paper shows that under some conditions the control exerted by a part of a metabolic network (a pathway) on a flux or concentration in any other part can be described through a single (overall) control coefficient. This has the following implications: (i) the relative contributions of a pathway enzyme to the regulation of the pathway (output) flux and of any flux or concentration outside are identical; therefore, the control analysis of the pathway 'in isolation' allows one to determine the control exerted by any pathway enzyme on the rest of the cell by estimation of the control efficient of just one, arbitrarily chosen enzyme; (ii) the relative control of any two metabolic variables outside the pathway (measured as the ratio of the control coefficients over these two variables outside) is the same for all pathway enzymes. These properties allow one to substitute effectively a pathway by a single (super)reaction and make it possible to consider such a pathway as a metabolic unit within the cellular enzyme network.

Cells↗

PubMed1991

Intermediate septal accessory pathways: electrocardiographic characteristics, electrophysiologic observations and their surgical implications.

Intermediate septal accessory pathways are located in close proximity to the atrioventricular (AV) node and His bundle, have unique features that distinguish them from typical anterior and posterior accessory pathways and have been associated with a high risk for unsuccessful pathway division and the production of complete AV block after surgery. Between July 1986 and May 1990, 4 of 70 patients (3 men and 1 woman; mean age 33 +/- 13 years) undergoing surgery for accessory pathway division were found to have an intermediate septal accessory pathway. The presenting arrhythmia was atrial fibrillation with rapid anterograde conduction over the accessory pathway in two patients and recurrent orthodromic reciprocating tachycardia in two patients. In all patients, the delta wave on the electrocardiogram (ECG) was inverted in lead V1, but two patterns of delta wave configuration were observed. In three patients (type 1 intermediate septal accessory pathway), the delta wave was upright in lead II, inverted in lead III and isoelectric in lead a VF; the transition from a negative to an upright delta wave occurred in lead V2. The fourth patient exhibited a different delta wave pattern (type 2 intermediate septal accessory pathway). The delta wave was upright in each of leads II, III and aVF; the transition from a negative to an upright delta wave occurred at lead V3. Intraoperative electrophysiologic study localized the atrial insertion of type 1 pathways to the midpoint of Koch's triangle close to the AV node.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

A simple technique for selective radiofrequency ablation of the slow pathway in atrioventricular node reentrant tachycardia.

OBJECTIVES: A simple technique was designed for radiofrequency ablation therapy of atrioventricular (AV) node reentrant tachycardia. BACKGROUND: This technique was based on the hypothesis that slow pathway conduction reflects conduction through the compact node and its posterior atrial input. METHODS: A total of 100 consecutive patients were studied; there were 37 men and 63 women, with a mean age of 48 +/- 15 years. All 100 patients had induction of sustained tachycardia with (51 patients) or without (49 patients) administration of isoproterenol or atropine, or both. The ablation catheter was initially manipulated to record the largest His bundle deflection from the apex of Koch's triangle. It was then curved downward and clockwise to the area of the compact node when His deflection was no longer visible and the ratio of atrial to ventricular electrogram was < 1. The radiofrequency current was delivered from the 4-mm tip electrode a mean of 5 +/- 7 times at a power of 25 +/- 4 W for a duration of 21 +/- 4 s. The total fluoroscopic time was 19 +/- 11 min. RESULTS: Selective ablation (56 patients) or modification (26 patients) of the slow pathway without affecting anterograde and retrograde fast pathway conduction was achieved in 82 patients. Ablation or modification of both the retrograde fast pathway and the slow pathway but with preservation of anterograde fast pathway conduction was noted in 12 patients. Ablation or modification of the retrograde fast pathway alone or both anterograde and retrograde fast pathway conduction was noted in three patients. Complete AV node block occurred in three patients. Seventy-three patients had no induction of echo beats or tachycardia and 24 patients had induction of a single echo beat after ablation. Follow-up study was performed in 62 patients 76 +/- 18 days after ablation. Thirty-nine patients had no induction of echo beats or tachycardia, 22 had induction of echo beats alone and 1 patient had induction of sustained tachycardia. CONCLUSION: Selective ablation of the slow AV node pathway can be achieved by a simple procedure with a high success rate and few complications.

Adolescent↗

PubMed1995

Localization and radiofrequency catheter ablation of left-sided accessory pathways during atrial fibrillation. Feasibility and electrogram criteria for identification of appropriate target sites.

OBJECTIVES: The purpose of the present study was to assess the feasibility of and electrophysiologic criteria for successful radiofrequency catheter ablation of left-sided accessory pathways during atrial fibrillation in patients with Wolff-Parkinson-White syndrome. BACKGROUND: The onset of recurrent or sustained atrial fibrillation can complicate or significantly prolong accessory pathway catheter ablation procedures. METHODS: We studied 19 consecutive patients (mean age [+/-SD] 44 +/- 16 years) with Wolff-Parkinson-White syndrome who had ongoing atrial fibrillation with rapid anterograde conduction over the accessory pathway (mean ventricular rate [+/-SD] 173 +/- 26 beats/min, range 130 to 220) at the beginning of the localization procedure during radiofrequency catheter ablation. Localization and ablation of the accessory pathway were performed with a 7F deflectable catheter (4-mm tip) that was placed underneath the mitral valve annulus. The electrophysiologic criteria from unipolar and bipolar local electrograms were compared for successful (n = 18) and unsuccessful (n = 39) sites. RESULTS: The accessory pathways were localized in the left posteroseptal (n = 6), posterior (n = 1), posterolateral (n = 7) and lateral (n = 5) regions and successfully ablated during atrial fibrillation in 18 (95%) of 19 patients with a mean of 3 +/- 2 radiofrequency pulses (range 1 to 8, median 2). Presence of an accessory pathway potential (94% vs. 44%), early activation time of the ventricular electrogram (-3.2 +/- 9.2 vs. -15.3 +/- 12.6 ms) and recording of atrial activation (88% vs. 61%) from the ablation catheter were helpful in identifying successful sites (p < 0.001, p < 0.001 and p < 0.05, respectively, compared with unsuccessful sites). In addition, the ventricular activation time in relation to the intrinsic deflection of the unipolar electrogram was significantly earlier at successful than unsuccessful sites (18.1 +/- 4.8 vs. 24.4 +/- 6.6 ms, p < 0.01). A QS complex on the unipolar electrogram was observed at 96% of successful sites and at 94% of unsuccessful sites (p = 0.74). Multivariate logistic regression analysis revealed that the presence of an accessory pathway potential (p < 0.002) and early ventricular activation time in relation to the onset of the QRS complex (p < 0.001) were independent predictors of ablation success. CONCLUSIONS: Localization and radiofrequency catheter ablation of left-sided accessory pathways is possible in patients with sustained atrial fibrillation and rapid anterograde conduction over the accessory pathway during the ablation procedure. The electrophysiologic criteria described here can be used to reliably identify successful sites for radiofrequency ablation.

Adult↗

PubMed1995

Epicardial electric shock ablation of the left lateral accessory pathway.

Fifty patients with drug-resistant, recurrent tachyarrhythmias causing Wolff-Parkinson-White syndrome underwent surgery between 1990 and 1992. All recognized surgical methods for accessory pathway destruction were performed. Epicardial electric shock ablation was first used as a method of surgically destroying an accessory atrioventricular pathway in 1983. This technique avoids the need for cardioplegia and hypothermia during operation. The procedure is based on the application of a series of two to five electrical shocks (50-150 J) to the region of the atrioventricular groove where the accessory pathway has been previously located. Some 32 patients with a left free wall accessory pathway underwent this operation. Cardioplegia and hypothermia were not required in 22 patients with an accessory pathway located in the left lateral position. In the second group comprising ten patients with a left lateral accessory pathway, four were diagnosed as having a second pathway and four had concomitant heart pathology such as coronary artery disease -- one had an atrial septal defect and another had a ventricular septal defect. Accessory pathway ablation was carried out in these ten patients using epicardial electric shock under normothermic cardiopulmonary bypass. Concomitant heart pathology was corrected at the second stage of the operation under cardiopulmonary bypass with cardioplegia and hypothermia. Postoperative electrophysiological studies confirmed that the accessory pathway had been destroyed in all patients. The only side effects of epicardial electric shock application were transient ST elevation < 1 mm in four patients, transient atrioventricular bloc in two and moderate sinus tachycardia in three.(ABSTRACT TRUNCATED AT 250 WORDS)

Catheter Ablation↗

PubMed2006

Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance.

The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf, PI3K, PTEN, Akt). Also, mutations occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. These pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of elevated activated Akt levels to phosphorylate and inactivate Raf-1. We have investigated the genetic structures and functional roles of these two signaling pathways in the malignant transformation and drug resistance of hematopoietic, breast and prostate cancer cells. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell-lineage-specific effects. Induced Raf expression can abrogate the cytokine dependence of certain hematopoietic cell lines (FDC-P1 and TF-1), a trait associated with tumorigenesis. In contrast, expression of activated PI3K or Akt does not abrogate the cytokine dependence of these hematopoietic cell lines, but does have positive effects on cell survival. However, activated PI3K and Akt can synergize with activated Raf to abrogate the cytokine dependence of another hematopoietic cell line (FL5.12) which is not transformed by activated Raf expression by itself. Activated Raf and Akt also confer a drug-resistant phenotype to these cells. Raf is more associated with proliferation and the prevention of apoptosis while Akt is more associated with the long-term clonogenicity. In breast cancer cells, activated Raf conferred resistance to the chemotherapeutic drugs doxorubicin and paclitaxel. Raf induced the expression of the drug pump Mdr-1 (a.k.a., Pgp) and the Bcl-2 anti-apoptotic protein. Raf did not appear to induce drug resistance by altering p53/p21Cip-1 expression, whose expression is often linked to regulation of cell cycle progression and drug resistance. Deregulation of the PI3K/PTEN/Akt pathway was associated with resistance to doxorubicin and 4-hydroxyl tamoxifen, a chemotherapeutic drug and estrogen receptor antagonist used in breast cancer therapy. In contrast to the drug-resistant breast cancer cells obtained after overexpression of activated Raf, cells expressing activated Akt displayed altered (decreased) levels of p53/p21Cip-1. Deregulated expression of the central phosphatase in the PI3K/PTEN/Akt pathway led to breast cancer drug resistance. Introduction of mutated forms of PTEN, which lacked lipid phosphatase activity, increased the resistance of the MCF-7 cells to doxorubicin, suggesting that these lipid phosphatase deficient PTEN mutants acted as dominant negative mutants to suppress wild-type PTEN activity. Finally, the PI3K/PTEN/Akt pathway appears to be more prominently involved in prostate cancer drug resistance than the Raf/MEK/ERK pathway. Some advanced prostate cancer cells express elevated levels of activated Akt which may suppress Raf activation. Introduction of activated forms of Akt increased the drug resistance of advanced prostate cancer cells. In contrast, introduction of activated forms of Raf did not increase the drug resistance of the prostate cancer cells. In contrast to the results observed in hematopoietic cells, Raf may normally promote differentiation in prostate cells which is suppressed in advanced prostate cancer due to increased expression of activated Akt arising from PTEN mutation. Thus in advanced prostate cancer it may be advantageous to induce Raf expression to promote differentiation, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK-induced proliferation. These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors.

Cell Line, Tumor↗

PubMed2006

Induction of interleukin-8 secretion and activation of ERK1/2, p38 MAPK signaling pathways by thrombin in dermal fibroblasts.

It was reported that thrombin could induce IL-8 secretion from human dermal fibroblasts (HDFs) through activation of proteinase activated receptor (PAR)-1. However, little is known of intracellular signaling pathways involved in the event. In the present study, expression of PARs in primarily cultured HDFs was determined by flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR), levels of IL-8 were determined by using ELISA and signaling pathways were examined by using Western blot. It was found that HDFs express PAR-1 and PAR-3, and thrombin induces approximately 7.4-fold increase in IL-8 secretion from HDFs. Hirudin and a PAR-1 blocking antibody completely abolish the action of thrombin. It was also found that PD98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor and U0126, an inhibitor of extracellular signal-regulated kinase (ERK) blocks thrombin-induced phosphorylation of ERK1/2 and IL-8 secretion, indicating the involvement of MAPK/ERK signaling pathway in thrombin-induced IL-8 secretion. p38 MAPK pathway appears also being involved as SB203580, a selective inhibitor of p38 MAPK inhibit phosphorylation of p38 MAPK and thrombin-induced IL-8 secretion. Furthermore, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, but not phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway may also be activated by thrombin. In conclusion, thrombin potently induce IL-8 release via PAR-1 from HDFs. Thrombin elicited IL-8 release is predominantly conducted through MAPK/ERK and p38 MAPK signaling pathways. Discovery of the signaling pathways of thrombin in HDFs may help to understand the role of thrombin in inflammation and tissue remodeling.

Adolescent↗

PubMed2004

Hedgehog signaling pathway as a therapeutic target in breast cancer.

The Hedgehog (Hh) signaling pathway, which is well conserved even in mammals and other vertebrate species, has long been known to direct growth and patterning during embryonic development. It has been shown that the Hh pathway also plays a critical role in mouse normal mammary gland development. Namely, it has been shown that disruption of the Hh pathway-related genes such as Patched-1 and Gli2 leads to ductal dysplasias that closely resemble some hyperplasia of human breast. In addition, it has been reported that breast carcinoma cells have disruption of these genes. These findings strongly indicate a contribution of the Hh pathway to development of human breast carcinoma. In fact, constitutive activation of the Hh pathway was found in most of 52 surgically resected breast carcinoma specimens. Interestingly, exposure to cyclopamine, a steroidal alkaroid that blocks the Hh pathway, suppressed the growth of the Hh pathway-activated breast carcinoma cells. Thus, the Hh pathway may function in progression of breast carcinoma. In this short review, possibilities of the Hh pathway as a new therapeutic target in breast carcinoma will be mainly discussed.

Animals↗

PubMed2005

Potential drug targets in Mycobacterium tuberculosis through metabolic pathway analysis.

The emergence of multidrug resistant varieties of Mycobacterium tuberculosis has led to a search for novel drug targets. We have performed an insilico comparative analysis of metabolic pathways of the host Homo sapiens and the pathogen M. tuberculosis. Enzymes from the biochemical pathways of M. tuberculosis from the KEGG metabolic pathway database were compared with proteins from the host H. sapiens, by performing a BLASTp search against the non-redundant database restricted to the H. sapiens subset. The e-value threshold cutoff was set to 0.005. Enzymes, which do not show similarity to any of the host proteins, below this threshold, were filtered out as potential drug targets. We have identified six pathways unique to the pathogen M. tuberculosis when compared to the host H. sapiens. Potential drug targets from these pathways could be useful for the discovery of broad spectrum drugs. Potential drug targets were also identified from pathways related to lipid metabolism, carbohydrate metabolism, amino acid metabolism, energy metabolism, vitamin and cofactor biosynthetic pathways and nucleotide metabolism. Of the 185 distinct targets identified from these pathways, many are in various stages of progress at the TB Structural Genomics Consortium. However, 67 of our targets are new and can be considered for rational drug design. As a case study, we have built a homology model of one of the potential drug targets MurD ligase using WHAT IF software. The model could be further explored for insilico docking studies with suitable inhibitors. The study was successful in listing out potential drug targets from the M. tuberculosis proteome involved in vital aspects of the pathogen's metabolism, persistence, virulence and cell wall biosynthesis. This systematic evaluation of metabolic pathways of host and pathogen through reliable and conventional bioinformatic methods can be extended to other pathogens of clinical interest.

Amino Acid Sequence↗

PubMed2005

Tailoring Ras-pathway--inhibitor combinations for cancer therapy.

Constitutive activation of Ras pathways plays a critical role in cancer development and maintenance. Inhibitors of such pathways are already in use for cancer therapy, with significant but as yet only partial success in the most deadly types of human cancers, against which even combinations of Ras-pathway inhibitors with classic cytotoxic drugs or irradiation are insufficient. Combinations of farnesyl transferase inhibitors (FTI's), inhibitors of Ras pathways, are now in use in clinical trials. In this review we analyze possible reasons for the limited efficacy--including the diverse and sometimes even contradictory effects of active Ras pathways in tumor cells--and propose possible alternative methods of tailoring Ras-pathway inhibitor combinations for cancer therapy. Such tailoring is now possible thanks to increased knowledge of the complexity of Ras pathways, their cooperation with other oncogenic pathways, and their "addictive" nature. We provide examples demonstrating that this knowledge can be translated into useful drug combinations that disrupt multiple oncogenic pathways and hit a weak point of a given tumor cell. One such example is combination treatment with a Ras inhibitor and a glycolysis blocker for pancreatic tumor cells. The future design of such potential drug combination therapies and the follow-up of their outcome will undoubtedly be facilitated by gene-expression profiling and proteomic methods.

Animals↗

PubMed2005

Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress.

Phosphorylation of eIF4E is associated with increased activity of the translational machinery. Oxidative stress of resident vascular cells and macrophages potently enhances eIF4E phosphorylation. Oxidative stress activates numerous intracellular signaling pathways, including MAP-family kinase pathways and pathways leading to S6 kinase activation. The activation of MAP-family kinase pathways leads to the activation of Mnk and hence eIF4E phosphorylation, whereas the S6 kinase pathway is not involved, based on insensitivity to its inhibitors rapamycin and wortmannin. Ca-dependent pathways have been implicated in eIF4E phosphorylation, but the oxidative stress response pathway targeting eIF4E does not appear to require their participation. The results suggest that the potent activation of ERK and p38 protein kinases is sufficient to account for the enhanced eIF4E phosphorylation. Either is independently sufficient to effect the change, as neither PD098059 (Erk pathway inhibitor) nor SB202190 (p38 pathway inhibitor) alone can block the response, but when combined the response is almost completely abrogated. Mnk activation by oxidative stress leading to enhanced eIF4E phosphorylation may play a role in promoting stress-induced hyperproliferative diseases, such as smooth muscle cell proliferation and hypertrophy in cardiovascular disease, as the synthesis of several key regulators of cell growth has been shown to be held in check by moderation of eIF4E activity.

Animals↗