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At least 883 records · Page 49Linked to original sources
PubMed2006

The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers.

PURPOSE OF REVIEW: There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers. RECENT FINDINGS: The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules. SUMMARY: The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.

Animals↗
PubMed2007

The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence.

Here we report that RNA interference against ATM inhibited p53 accumulation in cells expressing oncogenic STAT5 and cooperated with Rb inactivation to suppress STAT5A-induced senescence. Knocking down ATM was also effective to bypass E2F1-induced senescence and in combination with Rb inactivation, inhibited RasV12-induced senescence. Cells that senesced in response to ca-STAT5A or RasV12 accumulated DNA damage foci and activated ATM, ATR, Chk1, and Chk2, indicating that aberrant oncogene activation induces a DNA damage signaling response. Intriguingly, bypassing oncogene-induced senescence by inactivation of p53 and Rb did not eliminate the accumulation of oncogene-induced DNA damage foci (ODDI), suggesting a mechanism that may limit transformation in immortalized cells.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2002

Effect of a clinical pathway on selected clinical outcomes of pulmonary lobectomy.

BACKGROUND: North American hospitals use clinical care pathways to reduce length of stay, readmissions, and resource utilization and also to increase patient satisfaction. This study examined the effects of clinical pathways after pulmonary lobectomy in Taiwanese patients. METHODS: During 1997, a multidisciplinary team developed a lobectomy clinical pathway. The Program Evaluation Review Technique was used to analyze variances from the clinical pathway. Based on these findings, a standardized clinical pathway was implemented in late 1997. Forty patients participated. The variables of the study are length of hospital stay, readmission rates, spirometry usage, patient education and costs benefited from clinical care pathway use. RESULTS: Fourteen lobectomy patients following the clinical pathway had a mean length of stay of 17.9+/-4.18 days (p < 0.001) and 0% readmission (p < 0.001). Without a pathway, 26 lobectomy patients had a mean length of stay of 37.5+/-6.18 days and 18% were readmitted. Factors affecting clinical pathway success were preoperative days(p < 0.001), postoperative days (p = 0.033), spirometry usage (p = 0.043) and patient education (p = 0.02). Clinical pathway use reduced mean hospital costs by 16% for lobectomy. CONCLUSIONS: Length of hospital stay, readmission rates, spirometry usage, patient education and costs benefitted from clinical care pathway use. Factors critical to success appear to be multidisciplinary teamwork and communication.

Critical Pathways↗
PubMed1996

Immunosuppression induced by acute exposure to cocaine is dependent on metabolism by cytochrome P-450.

The primary objective of this paper was to characterize the role of metabolism in immunosuppression by acute exposure to cocaine. beta-Ionone has been used to study the role of metabolism in hepatotoxicity associated with acute exposure to cocaine, and was shown to produce a greater effect than other cytochrome P-450 (P-450) inducers. When beta-ionone (600 mg/kg s.c.) was pretreated 72 and 48 hr before the acute administration of cocaine (30 mg/kg i.p.) in B6C3F1 female mice, the antibody response to sheep red blood cells was significantly suppressed. Exposure to cocaine alone produced little or no suppression. The immunosuppression in cocaine + beta-ionone-treated mice was accompanied by a decrease in thymus weight and an increase in liver weight. Administration of metyrapone (40 mg/kg i.p.) 30 min before cocaine administration (40 mg/kg) blocked completely the suppression of the antibody response by cocaine in beta-ionone-pretreated mice. The reversal by metyrapone was additional evidence that a P-450 pathway was the critical metabolic pathway of cocaine to be immunosuppressive, and the inhibitory effect of metyrapone on cocaine N-demethylase was confirmed in liver microsomes. The inductive effects of beta-ionone were also characterized further. Cocaine N-demethylase activity was significantly induced by beta-ionone. The induction of P-450IIB1/2, the only isozyme shown previously to be associated with the hepatotoxicity by cocaine, was demonstrated by Western immunoblotting to be induced by beta-ionone at doses as low as 300 mg/kg; but was less than the induction associated with phenobarbital. Studies confirmed that acute exposure to cocaine also was immunosuppressive in phenobarbital-pretreated mice. Taken together, our present results suggest that the immunosuppression by acute exposure to cocaine is associated with the increased metabolism of cocaine to toxic metabolites by P-450, probably P-450IIB1/2, as demonstrated previously for its hepatotoxicity.

Animals↗
PubMed2005

[ISGF3, a critical factor of the IFN-alpha pathway in the antiviral action of HBV].

OBJECTIVE: To study the mechanism of signal transduction in anti-HBV action of IFN-alpha. METHODS: The HBV DNA in HepG 2.2.15 cell line supernatant with/without IFNalpha-2b were monitored by fluorescence real-time quantitive PCR. STAT1, STAT2, ISGF3-gamma, PKR, 2'5'-OAS mRNA levels from HepG 2 and HepG 2.2.15 cell lines that were treated with/without IFNalpha-2b at different times were detected by semi-quantitive RT-PCR. And the ISGF3-gamma protein was detected by Western blot. Then, these items were detected again after inhibiting the JAK-STAT pathway with genistein. RESULTS: The HBV DNA in 2215 supernatant that were treated with IFNalpha-2b for 8 hours decreased 0.72 log 10 copies/ml. But the basal levels of DNA in cells pretreated with genistein? followed by IFNalpha-2b did not decrease. The STAT1, STAT2, ISGF3-gamma, 2'5'-OAS, PKR mRNA levels were upregulated by IFNalpha-2b. The same phenomena were observed with STAT1, STAT2, ISGF3-gamma mRNA when pretreated with genistein then treated with IFNalpha-2b, but the levels of 2'5'-OAS, PKR mRNA were decreased in this situation. The expression of the protein of ISGF3-gamma was also augmented by IFNalpha-2b, and was blocked by genistein. CONCLUSION: The JAK-STAT pathway seems to be a critical pathway in IFNalpha-2b action against HBV? and ISGF3 is most probably a key factor of the route.

Antiviral Agents↗
PubMed1997

New understanding of the pathogenesis of CML: a prototype of early neoplasia.

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210bcr/abl. Relative to normal c-abl, p210bc1/abl has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease.

Adolescent↗
PubMed2004

c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways.

A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-gamma had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.

Animals↗
PubMed2000

Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC.

The solid growth of high-grade glioma appears to be critically dependent on tumor angiogenesis. It remains unknown, however, whether the diffuse infiltration of glioma cells into healthy adjacent tissue is also dependent on the formation of new tumor vessels. Here, we analyze the relationship between tumor angiogenesis and tumor cell infiltration in an experimental glioma model. C6 cells were implanted into the dorsal skinfold chamber of nude mice, and tumor angiogenesis was monitored by intravital fluorescence videomicroscopy. Glioma infiltration was assessed by the extent of tumor cell invasion into the adjacent chamber tissue and by expression of SPARC, a cellular marker of glioma invasiveness. To test the hypothesis that glioma angiogenesis and glioma infiltration are codependent, we assessed tumor infiltration in both the presence and the absence of the angiogenesis inhibitor SU5416. SU5416 is a selective inhibitor of the VEGF/Flk-1 signal-transduction pathway, a critical pathway implicated in angiogenesis. Control tumors demonstrated both high angiogenic activity and tumor cell invasion accompanied by strong expression of SPARC in invading tumor cells at the tumor-host tissue border. SU5416-treated tumors demonstrated reduced vascular density and vascular surface in the tumor periphery accompanied by marked inhibition of glioma invasion and decreased SPARC expression. A direct effect of SU5416 on glioma cell motility and invasiveness was excluded by in vitro migration and invasion assays. These results suggest a crucial role for glioma-induced angiogenesis as a prerequisite for diffuse tumor invasion and a possible therapeutic role for anti-angiogenic compounds as inhibitors of both solid and diffuse infiltrative tumor growth.

Angiogenesis Inhibitors↗
PubMed2006

An integrated care pathway to save the critically ischaemic diabetic foot.

This prospective study describes and evaluates the efficacy of an integrated care pathway for the management of the critically ischaemic diabetic foot patients by a multidisciplinary team. A weekly joint diabetes/vascular/podiatry ward round and outpatient clinic was established where patients were assessed within 7 days of referral by clinical examination, ankle-brachial-index-pressures, duplex angiogram and transcutaneous oxygen pressures. An angiogram +/- angioplasty or alternatively a magnetic resonance angiography prior to surgical revascularisation was performed in patients deemed not suitable for angioplasty based on the above vascular assessment. Between January 2002 and June 2003(18 months), 128 diabetic patients with lower limb ischaemia were seen. Thirty-four (26.6%) patients received medical treatment alone, and 18 (14.1%) were deemed 'palliative' due to their significant co-morbidities. The remaining 76 (59.4%) patients underwent either angioplasty (n = 56), surgical reconstruction (n = 18), primary major amputation (n = 2) or secondary amputation after surgical revascularisation (n = 1). Minor toe amputations were required in 35 patients. The mortality in the intervention group was 14% (11/76). This integrated multidisciplinary approach offers a consistent and equitable service to diabetic patients with critically ischaemic feet and appears to have a beneficial major/minor amputation ratio.

Adult↗
PubMed2004

The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1.

The metabolic actions of insulin are transduced through the phosphatidylinositol 3-kinase pathway. A critical component of this pathway is 3-phosphoinositide-dependent kinase-1 (PDK-1), a PH domain-containing enzyme that catalyzes the activating phosphorylation for many AGC kinases, including Akt and protein kinase C isozymes. We used a directed proteomics-based approach to identify the adaptor protein Grb14, which binds the insulin receptor through an SH2 domain, as a novel PDK-1 binding partner. Interaction of these two proteins is constitutive and mediated by a PDK-1 binding motif on Grb14. Disruption of this motif by point mutation or deletion of the Grb14 SH2 domain prevents the insulin-triggered membrane translocation of PDK-1. The interaction of PDK-1 with Grb14 facilitates Akt function: disruption of the interaction by overexpression of a construct of Grb14 mutated in the PDK-1 binding motif significantly decreases insulin-dependent activation of Akt. Thus, Grb14 serves as an adaptor protein to recruit PDK-1 to activated insulin receptor, thus promoting Akt phosphorylation and transduction of the insulin signal.

3-Phosphoinositide-Dependent Protein Kinases↗