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At least 19 recordsLinked to original sources
PubMed1989

Two pathways for inducing interleukin 2 production in MOLT 16 cells, a human leukemic T-cell line: interleukin 1 pathway and interleukin 1-independent pathway.

Phytohemagglutinin (PHA)-stimulated MOLT 16 cells (a human leukemic T cell line, at a concentration of 2 x 10(6) cells/ml) secreted 6 U/ml of interleukin 2 (IL 2) into the culture supernatant during 24 h culture. When interleukin 1 (IL 1) (5 U/ml) or IL 1-producing cells such as human T cell leukemia virus-1 (HTLV-1)-transformed T cell line, C5/MJ, and myelomonocytic cell line, THP-1-O, were added to the MOLT 16 culture at a concentration of 4 x 10(5) cells/ml, far greater IL 2 production (greater than 65 U/ml) was observed. The activity of soluble IL 1 and membrane-associated IL 1 produced by these accessory (A) cells was completely neutralized by the treatment with anti-human IL 1 antibody. In sharp contrast, MOLT 16 cells co-cultured with BALL-1 cells (a human leukemic B cell line) resulted in comparable increases in IL 2 production (175 U/ml), although no IL 1 or IL 1-like activity was detected either in the supernatants or in the cell lysates of BALL-1 cells. An augmentation of IL 2 production was also induced with paraformaldehyde-fixed BALL-1 cells, and this augmentation could not be inhibited by anti-human IL 1 antibody. These data indicate that MOLT 16 provides a model for determining pathways for activating T cells leading to IL 2 production in response to mitogens. Two pathways have been described in the report: one involving secreted or membrane-associated IL 1, and a second independent pathway which involves contact of surface membranes in the presence of PHA.

Antigens, Surface↗
PubMed1988

New catheter technique for recording left free-wall accessory atrioventricular pathway activation. Identification of pathway fiber orientation.

The ability to record accessory atrioventricular (AV) pathway activation consistently may be uniquely beneficial in improving pathway localization, identifying anatomic relations, and providing insight into unusual conduction properties. For the purpose of recording left AV accessory pathway activation, an electrode catheter was specially designed for use in the coronary sinus. The orthogonal catheter has three sets of four electrodes spaced evenly around the circumference. Electrograms were recorded at low gain (less than 1 cm/mV) between adjacent electrodes on the same set (interelectrode distance, 1.5 mm, center to center). This provides a recording dipole perpendicular to the atrioventricular groove to enhance recording of accessory pathway activation while minimizing overlapping atrial or ventricular potentials. The orthogonal electrode catheter was used in the electrophysiological study of 48 consecutive patients with 59 left AV accessory pathways. The catheter could be advanced along the coronary sinus beyond the site of earliest retrograde atrial activation in 49 of the 59 accessory pathways. Activation potentials were recorded from 45 of the 49 (92%) accessory pathways accessible to the catheter (5 of 5 anterior, 8 of 8 anterolateral, 15 of 16 lateral, 5 of 5 posterolateral, 5 of 5 posterior, and 7 of 10 posteroseptal). Accessory pathway potentials were validated by dissociating them from both atrial and ventricular activation by programmed-stimulation techniques. During surgery, accessory pathway potentials were identified from orthogonal catheter electrodes in the coronary sinus in 14 of 16 accessory pathways (12 patients). Epicardial mapping confirmed the location of the accessory pathway, and direct pressure over the orthogonal catheter electrode that recorded the accessory pathway potential resulted in transient conduction block in nine of the 14 accessory pathways. Orthogonal electrode maps of the coronary sinus identified an oblique course in 39 of 45 recorded accessory pathways. Thirty-two of 38 left free-wall accessory pathways were oriented with atrial insertion 4-30 mm (median, 14 mm) proximal (posterior) to the ventricular insertion. In the remaining six free-wall accessory pathways, the lateral excursion could not be determined because either only the atrial end of the accessory pathway was recorded or activation of multiple pathway fibers prevented tracking of individual strands. The seven recorded posteroseptal pathways exhibited accessory pathway potentials throughout an 8-18-mm (median, 10 mm) length of the proximal coronary sinus, but fiber orientation was difficult to determine.(ABSTRACT TRUNCATED AT 400 WORDS)

Atrioventricular Node↗
PubMed1990

IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway.

IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.

Adenylyl Cyclase Inhibitors↗
PubMed1975

Determinants of fast- and slow-pathway conduction in patients with dual atrioventricular nodal pathways.

Electrophysiological studies were performed in two patients with documented paroxysmal supraventricular tachycardia and dual atrioventricular (AV) nodal pathways as defined by the atrial extra-stimulus technique. Both patients manifested two ranges of A-H intervals (AV nodal conduction times) at critical cycle lengths, reflecting fast- and slow-pathway conduction. The occurrence of fast- and slow-pathway conduction at the same cycle length depended on a long fast-pathway effective refractory period relative to the spontaneous or driven cycle length. At critical cycle lengths with fast-pathway conduction, a shift to slow-pathway conduction could be induced by a premature atrial impulse falling within the effective refractory period of the fast pathway. Repetitive retrograde concealed conduction to the fast pathway then maintained antegrade slow-pathway conduction. Resumption of fast-pathway conduction was induced with premature atrial impulses falling within the effective refractory periods of both the fast and the slow pathways, allowing recovery of the fast pathway for antegrade conduction. Atrial echoes and AV nodal reentrant paroxysmal supraventricular tachycardia occurred when sufficient slow-pathway delay was achieved to allow recovery of the fast pathway for retrograde conduction.

Atrioventricular Node↗
PubMed1985

Pseudosimultaneous fast and slow pathway conduction: a common electrophysiologic finding in patients with dual atrioventricular nodal pathways.

Two ventricular responses following termination of rapid atrial pacing were noted in 24 of 87 patients with dual atrioventricular (AV) nodal pathways and supraventricular tachycardia. In all 24 patients, the AH intervals of the first and second ventricular responses were comparable with those of the fast and slow pathways, respectively. Careful analysis of the whole pacing sequence revealed that, in 21 patients, this phenomenon resulted from sustained slow pathway conduction with long AH intervals. In these patients, as the AH interval of each paced beat was progressively lengthened during pacing, the corresponding His bundle and ventricular responses were pushed one cycle behind the current atrial paced beat, so that the last paced beat was followed by two His bundle and ventricular responses. In only three patients did double ventricular responses result from simultaneous fast and slow pathway conduction. One of these three patients also showed two ventricular responses resulting from sustained slow pathway conduction. Several factors predispose to the occurrence of this phenomenon in patients with dual AV nodal pathways. These include an ability to sustain slow pathway conduction, a longer slow pathway AH interval, a shorter sinus AH interval (fast pathway) and a shorter atrial paced cycle length that sustains slow pathway conduction. In conclusion, sustained slow pathway conduction with resultant long AH intervals is the mechanism of two ventricular responses following termination of atrial pacing in most patients with dual AV nodal pathways. This phenomenon should be distinguished from the rare occurrence of double ventricular responses to an atrial impulse due to simultaneous fast and slow pathway conduction.

Adolescent↗
PubMed1990

Retrograde dual atrioventricular nodal pathway in patients with atrioventricular reciprocating tachycardia using concealed accessory pathways.

We present electrophysiological studies in two patients with atrioventricular reciprocating tachycardias. The first patient had anterograde dual atrioventricular nodal pathways with a right-sided concealed accessory pathway. The retrograde atrioventricular nodal pathway showed evidence suggestive of slow pathway properties. After block was induced with ajmaline in the accessory pathway, a typical pattern of discontinuous retrograde atrioventricular nodal conduction curves was recognized. We then observed three types of induced atrioventricular reentry. The other patient had continuous anterograde atrioventricular nodal conduction, a fast-conducting retrograde atrioventricular nodal pathway and a left-sided concealed accessory pathway. After refractoriness had been induced in the accessory pathway with ajmaline, a typical pattern of retrograde dual atrioventricular nodal pathways was recognized, and it proved impossible to induce atrioventricular nodal echoes. Induction of block or impairment of conduction with ajmaline in the concealed accessory pathway proved helpful in the disclosure of retrograde dual atrioventricular nodal pathways by means of the ventricular extrastimulus method.

Adolescent↗
PubMed1992

Clinical characteristics and electrophysiologic properties of atrioventricular accessory pathways: importance of the accessory pathway location.

OBJECTIVES: This study was designed to assess the influence of accessory atrioventricular (AV) pathway location on the clinical and electrophysiologic characteristics of 384 consecutive symptomatic patients having a single accessory pathway. METHODS: Four locations were studied: left free wall (n = 270), posteroseptal (n = 52), anteroseptal (n = 29) and right free wall (n = 33). Ten clinical variables and 12 electrophysiologic variables were analyzed, including the effective refractory period of the accessory pathway and the different clinically occurring and inducible arrhythmias. RESULTS: Only two clinical findings were associated with accessory pathway location: 1) later age at onset of symptoms in the left free wall versus other accessory pathway locations (24 +/- 12 vs. 20 +/- 11 years, p = 0.02), and 2) later age at the time of electrophysiologic study in the left free wall accessory pathway location (36 +/- 13 vs. 32 +/- 11 years, p = 0.01). Six electrophysiologic variables showed a correlation with the accessory pathway location: 1) retrograde conduction only was found less frequently in right free wall (9%) and anteroseptal (10%) than in left free wall (26%) and posteroseptal (29%) accessory pathway locations (p = 0.05); 2) the retrograde effective refractory period of the accessory pathway was shorter in anteroseptal (253 +/- 52 ms) and left free wall (270 +/- 72 ms) as compared with right free wall (296 +/- 101 ms) and posteroseptal (301 +/- 76 ms) locations (p = 0.05); 3) retrograde decremental conduction over the accessory pathway was present in the posteroseptal (17%) and left free wall (3%) but absent in the other locations (p less than 0.001); 4) anterograde decremental conduction was only seen in the right free wall location (12%) (p less than 0.001); 5) orthodromic reentrant tachycardia was induced less frequently in the right free wall than in other locations (70% vs. 93%, p less than 0.001); and 6) inducibility of atrial fibrillation was greater in anteroseptal (62%) than in right free wall (21%), left free wall (44%) and posteroseptal (36%) locations (p = 0.01). CONCLUSIONS: The location of the accessory AV pathway is associated with specific electrophysiologic characteristics.

Adolescent↗
PubMed1969

The pentose phosphate pathway of glucose metabolism. Enzyme profiles and transient and steady-state content of intermediates of alternative pathways of glucose metabolism in Krebs ascites cells.

1. The pentose phosphate pathway in Krebs ascites cells was investigated for regulatory reactions. For comparison, the glycolytic pathway was studied simultaneously. 2. Activities of the pentose phosphate pathway enzymes were low in contrast with those of the enzymes of glycolysis. The K(m) values of glucose 6-phosphate dehydrogenase for both substrate and cofactor were about four times the reported upper limit for the enzyme from normal tissues. Fructose 1,6-diphosphate and NADPH competitively inhibited 6-phosphogluconate dehydrogenase. 3. About 28% of the hexokinase activity was in the particulate fraction of the cells. The soluble enzyme was inhibited by fructose 1,6-diphosphate and ribose 5-phosphate, but not by 3-phosphoglycerate. The behaviour of the partially purified soluble enzyme in vitro in a system simulating the concentrations of ATP, glucose 6-phosphate and P(i) found in vivo is reported. 4. Kinetics of metabolite accumulation during the transient state after the addition of glucose to the cells indicated two phases of glucose phosphorylation, an initial rapid phase followed abruptly by a slow phase extending into the steady state. 5. Of the pentose phosphate pathway intermediates, accumulation of 6-phosphogluconate, sedoheptulose 7-phosphate and fructose 6-phosphate paralleled the accumulation of glucose 6-phosphate. Erythrose 4-phosphate reached the steady-state concentration by 2min., whereas the pentose phosphates accumulated linearly. 6. The mass-action ratios of the pentose phosphate pathway reactions were calculated. The transketolase reaction was at equilibrium by 30sec. and then progressively shifted away from equilibrium towards the steady-state ratio. The glucose 6-phosphate dehydrogenase was far from equilibrium at all times. 7. Investigation of the flux of [(14)C]glucose carbon confirmed the existence of an operative pentose phosphate pathway in ascites cells, contributing 1% of the total flux in control cells and 10% in cells treated with phenazine methosulphate. 8. The pentose phosphate formed by way of the direct oxidative route and estimated from the (14)CO(2) yields represented 20% of the total accumulated pentose phosphate, the other 80% being formed by the non-oxidative reactions of the pentose phosphate pathway. 9. The pentose phosphate pathway appears to function as two separate pathways, both operating towards pentose phosphate formation. Control of the two pathways is discussed.

Adenosine Triphosphate↗
PubMed1989

Localization of left free-wall and posteroseptal accessory atrioventricular pathways by direct recording of accessory pathway activation.

With the advent of catheter ablation techniques, precise localization of accessory AV pathways (AP) assumes greater importance. In an effort to define the course of AP fibers, we attempted to record activation of 56 left free-wall and 23 posteroseptal APs in 62 patients undergoing electrophysiological study. The coronary sinus (CS) and great cardiac vein (GCV) were mapped using orthogonal catheter electrodes, which provide a recording dipole perpendicular to the AV groove. The tricuspid annulus (TA) was mapped using a 2 mm spaced octapolar electrode catheter. Potentials were considered to represent AP activation only if they could be dissociated from both atrial and ventricular activation by programmed stimulation. Orthogonal catheter electrodes in the CS and GCV were advanced beyond the site of earliest retrograde atrial activation and/or earliest antegrade ventricular activation in 45 of the 56 left free-wall APs, and AP potentials were recorded from 42 (93%). An oblique course was identified in 36 APs, with the ventricular insertion being recorded 4-30 mm (median 15 mm) distal or anterior to the atrial insertion. In three patients, antegrade and retrograde conduction proceeded over different (but close) parallel fibers. AP potentials were recorded from 19 of 23 posteroseptal pathways. Ten pathways (left posteroseptal) were recorded from the CS, beginning 5-11 mm (median 9 mm) distal to the os, with potentials extending 8-18 mm (median 11 mm) distally. Four pathways (mid-septal) were recorded along the TA, anterior to the CS ostium and posterior to the His bundle catheter. Five pathways (right posteroseptal) were recorded along the TA, directly opposite or immediately posterior to the CS ostium. One of the patients had both midseptal and left posteroseptal pathways and three patients had both right posteroseptal and left posteroseptal pathways. We conclude: 1) left free-wall APs transit the AV groove obliquely and may be comprised of multiple, closely spaced, parallel fibers; 2) the anatomical location of "posteroseptal" pathways is variable and the presence of fibers at multiple sites is common; and 3) direct recordings of AP activation facilitate tracking of the accessory pathway along its course from atrium to ventricle and help identify the presence of multiple fibers.

Action Potentials↗
PubMed2025

Genome-wide screening in human embryonic stem cells identifies genes and pathways involved in the p53 pathway.

BACKGROUND: The tumor suppressor protein, p53, which is mutated in half of human tumors, plays a critical role in cellular responses to DNA damage and maintenance of genome stability. Therefore, increasing our understanding of the p53 pathway is essential for improving cancer treatment and diagnosis. METHODS: This study, which aimed to identify genes and pathways that mediate resistance to p53 upregulation, used genome-wide CRISPR-Cas9 loss-of-function screening done with Nutlin-3a, which inhibits p53-MDM2 interaction, resulting in p53 accumulation and apoptotic cell death. We used bioinformatics analysis for the identification of genes and pathways that are involved in the p53 pathway and cell survival assays to validate specific genes. In addition, we used RNA-seq to identify differentially expressed p53 target genes in gene knockout (KO) cell lines. RESULTS: Our screen revealed three significantly enriched pathways: The heparan sulfate glycosaminoglycan biosynthesis, diphthamide biosynthesis and Hippo pathway. Notably, TRIP12 was significantly enriched in our screen. We found that TRIP12 is required for the p53-dependent transcription of several pro-apoptotic genes. CONCLUSION: Our study has identified two novel pathways that play a role in p53-mediated growth restriction. Moreover, we have highlighted the interaction between the Hippo and the p53 pathways. Interestingly, we have shown that TRIP12 plays an important function in the p53 pathway by selectively affecting its role as a transcription factor.

Humans↗
PubMed1991

Atrial fibrillation in patients with an accessory pathway: importance of the conduction properties of the accessory pathway.

To investigate how the electrophysiologic properties of the accessory pathway affect the occurrence of atrial fibrillation in the Wolff-Parkinson-White syndrome, programmed stimulation data of 57 patients with overt pre-excitation and 33 patients with a concealed accessory pathway with documented circus movement tachycardia were reviewed. Atrial fibrillation had occurred spontaneously in 31 (54%) of the 57 patients with the Wolff-Parkinson-White syndrome and in 1 (3%) of the 33 with a concealed accessory pathway (p less than 0.001). Sustained atrial fibrillation was induced in 23 of 31 patients with the Wolff-Parkinson-White syndrome and spontaneous atrial fibrillation (Group A), in 7 of 26 patients with the Wolff-Parkinson-White syndrome without spontaneous atrial fibrillation (Group B) and in 5 of 33 patients with a concealed accessory pathway (Group C). The anterograde effective refractory period of the accessory pathway was shorter in Group A than in Group B (252 versus 297 ms, p less than 0.001). There were no differences among groups in PA interval, right to left atrium conduction time, cycle length of tachycardia and atrial and retrograde accessory pathway effective refractory period. Atrial fibrillation is more frequent in patients with the Wolff-Parkinson-White syndrome than in those with a concealed accessory pathway. Patients with overt pre-excitation and atrial fibrillation have a shorter anterograde accessory pathway refractory period. It seems therefore that the anterograde rather than the retrograde conduction properties of the accessory pathway are the critical determinants of atrial fibrillation in the Wolff-Parkinson-White syndrome.

Adult↗
PubMed1987

Paroxysmal nonreentrant supraventricular tachycardia due to simultaneous fast and slow pathway conduction in dual atrioventricular node pathways.

Electrophysiologic studies were performed on a 49 year old woman who had paroxysmal nonreentrant supraventricular tachycardia due to simultaneous anterograde conduction through dual atrioventricular (AV) node pathways. Slow pathway conduction was inversely related to the preceding sinus cycle length and fast pathway conduction was determined by the Hs-A interval (measured from the His potential due to slow pathway conduction to the onset of the subsequent atrial electrogram). Major determinants of sustained simultaneous anterograde fast and slow pathway conduction during sinus rhythm were 1) a retrograde unidirectional block in both fast and slow pathways, and 2) a critical conduction delay in the slow pathway and a long enough Hs-A interval to allow sequential conduction of impulse from both pathways. Flecainide was successful in preventing recurrences of the tachycardia by eliminating slow pathway conduction during long-term follow-up.

Atrioventricular Node↗
PubMed2026

Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.

INTRODUCTION: Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments. METHODS: Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays. RESULTS: A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways. DISCUSSION: These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation. CONCLUSION: Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.

Diosmetin↗
PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗
PubMed1988

Growth cone guidance by substrate-bound laminin pathways is correlated with neuron-to-pathway adhesivity.

Substrate-bound laminin pathways prepared by the method of Hammarback et al. [J.A. Hammarback, S.L. Palm, L.T. Furcht, and P.C. Letourneau (1985). J. Neurosci. Res. 13, 213-220] guided peripheral nervous system neurites (dissociated dorsal root ganglia and sympathetic ganglia) and central nervous system neurites (dissociated spinal cord and brain). Guidance of individual growth cones by 7- to 10-micron-wide laminin pathways was observed using time-lapse video microscopy. Fibronectin pathways, produced by the method used for laminin pathways, did not guide neurites. The guidance effect of laminin pathways was quantified and found to correlate with the concentration of laminin initially applied to the substratum. The concentration of laminin initially applied to the substratum also correlated with increased adhesivity of dorsal root ganglia (DRG) neurons to laminin constituting the pathways relative to uv-irradiated laminin that borders the pathways. The guidance effect of laminin pathways was blocked by anti-laminin antibodies or by laminin but not by anti-fibronectin antibodies. This study demonstrates that guidance of DRG neurites by laminin occurs at the growth cone in a manner consistent with the hypothesis of guidance by differential neuron-to-substratum adhesivity.

Animals↗
PubMed1989

Pre- and intraoperative identification of multiple accessory pathways. Experience of 19 pathways in 9 patients.

The pre- and intraoperative electrophysiological studies in 9 patients with two or more accessory pathways are described. The presence of multiple accessory pathways was clinically suspected in only 2 patients. During the preoperative electrophysiological study two accessory pathways were identified in 7 patients and a single pathway in 2 patients. At operation, additionally three accessory pathways were identified in 3 patients. One out of two pathways, found preoperatively, could not be confirmed in 1 patient. It is concluded that the clinical or preoperative electrophysiological evidence of only one accessory pathway should not distract one's attention from considering multiple accessory pathways in patients presenting only one type of tachycardia.

Electrophysiology↗
PubMed1991

Cross-regulation between G-protein-mediated pathways. Activation of the inhibitory pathway of adenylylcylclase increases the expression of beta 2-adrenergic receptors.

Cross-regulation from the stimulatory (Gs alpha)-mediated) to the inhibitory (Gi alpha-mediated) pathways controlling adenylylcyclase has been described (Hadcock, J. R., Ros, M., Watkins, D. C., and Malbon, C. C. (1990) J. Biol. Chem. 265, 14784-14790). The extent to which cross-regulation occurs from inhibitory to stimulatory pathways for adenylylcyclase was explored. Persistent activation of the inhibitory pathway of adenylylcyclase by the A1-adenosine receptor agonist (-)-N6 (R-phenylisopropyl) adenosine (PIA) in hamster smooth muscle DDT1 MF-2 cells enhanced the stimulatory pathway of adenylylcyclase and its activation by the beta 2-adrenergic receptor agonist isoproterenol. PIA treatment (48 h) of cells increased isoproterenol-stimulated adenylylcyclase by 2-fold. In addition, the ED50 for stimulation of adenylylcyclase by isoproterenol decreased 50-fold to approximately 1 nM. Persistent activation of cells with PIA increased beta 2-adrenergic receptor number in a time- and dose-dependent manner. The steady-state levels of beta 2-adrenergic receptors (radioligand binding and immunoblotting) and receptor mRNA levels increased by more than 70%, while the half-life of the receptor (24 h) was unaltered. Both A1-adenosine receptor binding and Gi alpha 2 levels declined by half in cells persistently activated with PIA. Although Gi alpha 2 mRNA levels and the relative rate of synthesis of Gi alpha 2 protein upon persistent activation of the inhibitory pathway were found to increase, a decrease in the half-life of Gi alpha 2 from approximately 75 h in naive cells to approximately 40 in cells provides the basis for the decline in Gi alpha 2 levels. The steady-state level of mRNA and half-life of Gs alpha protein were unaltered in persistently activated cells. Thus, activation of the inhibitory pathway of adenylylcyclase cross-regulates the stimulatory, hormone-sensitive adenylylcyclase system by: (i) up-regulating beta 2-adrenergic receptors and enhancing the activation of the stimulatory adenylylcyclase pathway and (ii) down-regulating elements of the inhibitory adenylylcyclase pathway (Gi alpha 2 and A1-adenosine receptor binding).

Adenosine↗
PubMed1987

Shunting of insulin from a retroendocytotic pathway to a degradative pathway by sodium vanadate.

Adipocytes route internalized insulin through two major pathways, a degradative pathway and a retroendocytotic pathway. To examine whether sorting of incoming insulin-receptor complexes can be altered, we assessed the effect of vanadate on the intracellular processing of both insulin and insulin receptors. After cells were pretreated with vanadate (1 mM for 30 min at 37 degrees C), 125I-insulin was loaded into the cell interior. When the net efflux of insulin from cells into the medium was then monitored, vanadate was found to slow the efflux of insulin from a t1/2 of 6.2 min (controls) to 11 min. Since efflux reflects both the rapid extrusion of intact insulin and the slower release of degradative products, we proposed that vanadate diverts more insulin into the degradative pathway. Further evidence in support of this idea included the following: 1) when intracellular degradation of insulin was impaired by chloroquine, undegraded insulin accumulated faster within vanadate-treated cells, consistent with greater flux through a degradative pathway; 2) vanadate increased the percentage of degraded insulin released from cells from 61 and 72%; and 3) under steady-state binding conditions, more insulin resided in the cell interior of vanadate-treated cells (44.8% versus 34.5%), and the time required for the intracellular pool to reach equilibrium was prolonged (t1/2 of 5.5 min versus 4.0). Neither insulin internalization nor degradation was impaired by vanadate alone. In related studies Tris was found to inhibit insulin-mediated receptor recycling by only 10%, whereas in the presence of vanadate (plus Tris) almost all incoming insulin receptors were prevented from recycling. Vanadate alone had no effect on the ability of insulin receptors to recycle. Based on these results we conclude that: 1) vanadate shunts incoming insulin from a more rapid retroendocytotic pathway to a slower degradative pathway and diverts insulin receptors from a Tris-insensitive recycling pathway to one that can be completely inhibited by Tris; 2) these effects are selective, in that vanadate impairs neither insulin degradation nor receptor uptake and recycling. Considered together, these findings support the idea that a sorting mechanism exists for the intracellular routing of incoming insulin-receptor complexes.

Adipose Tissue↗