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Direct Pathway (direct + pathway)
Selected AbstractsA pathway through interferon-, is the main pathway for induction of nitric oxide upon stimulation with bacterial lipopolysaccharide in mouse peritoneal cellsFEBS JOURNAL, Issue 19 2003Motohiro Matsuura Production of nitric oxide (NO) in response to bacterial lipopolysaccharide (LPS) was investigated using cultures of mouse peritoneal exudate cells (PEC) and the macrophage cell line RAW264.7. In the presence of anti-(interferon-,) (IFN-,), NO production was markedly suppressed in the PEC culture but not in the RAW264.7 culture. In the PEC culture, LPS induced both IFN-, production and activation of IFN response factor-1, which leads to the gene expression of inducible NO synthase, but neither was induced in the culture of RAW264.7 cells. In addition to anti-(IFN-,), antibodies against interleukin (IL)-12 and IL-18 showed a suppressive effect on LPS-induced NO production in the PEC culture, and these antibodies in synergy showed strong suppression. Stimulation of the PEC culture with IL-12 or IL-18 induced production of IFN-, and NO, and these cytokines, in combination, exhibited marked synergism. Stimulation of the culture with IFN-, induced production of NO, but not IL-12. The macrophage population in the PEC, prepared as adherent cells, responded well to LPS for IL-12 production, but weakly for production of IFN-, and NO. The macrophages also responded well to IFN-, for NO production. For production of IFN-, by stimulation with LPS or IL-12 + IL-18, nonadherent cells were required in the PEC culture. Considering these results overall, the indirect pathway, through the production of intermediates (such as IFN-,-inducing cytokines and IFN-,) by the cooperation of macrophages with nonadherent cells, was revealed to play the main role in the LPS-induced NO production pathway, as opposed to the direct pathway requiring only a macrophage population. [source] Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4,AKT,ATP-binding cassette G2 pathway,HEPATOLOGY, Issue 2 2010Xiao Qi Wang Chemoresistance presents a major obstacle to the efficacy of chemotherapeutic treatment of cancers. Using chemotherapeutic drugs to select drug-resistant cancer cells in hepatocellular carcinoma (HCC) and several other cancer cell lines, we demonstrate that chemoresistant cells displayed cancer stem cell features, such as increased self-renewal ability, cell motility, multiple drug resistance, and tumorigenicity. Octamer 4 (Oct4) messenger RNA (mRNA) levels were dramatically increased in chemoresistant cancer cells due to DNA demethylation regulation of Oct4. By functional study, Oct4 overexpression enhanced whereas Oct4 knockdown reduced liver cancer cell resistance to chemotherapeutic drugs in vitro and in xenograft tumors. It is known that the Oct4-TCL1-AKT pathway acts on embryonic stem cells and cancer stem cells in cell proliferation through inhibition of apoptosis. We further demonstrate that Oct4 overexpression induced activation of TCL1, AKT, and ABCG2 to mediate chemoresistance, which can be overcome by addition of the PI3K/AKT inhibitor; therefore, a direct pathway of Oct4-TCL1-AKT-ABCG2 or a combination of Oct4-TCL1-AKT with the AKT-ABCG2 pathway could be a potential new mechanism involved in liver cancer cell chemoresistance. Moreover, the clinical significance of the Oct4-AKT-ABCG2 pathway can be demonstrated in HCC patients, with a strong correlation of expression patterns in human HCC tumors. The role of the Oct4-AKT-ABCG2 axis in cancer cell chemoresistant machinery suggests that AKT pathway inhibition (PI3K inhibitors) not only inhibits cancer cell proliferation, but may also enhance chemosensitivity by target potential chemoresistant cells. Conclusion: Oct4, a transcriptional factor of pluripotent cells, can mediate chemoresistance through a potential Oct4-AKT-ABCG2 pathway. (HEPATOLOGY 2010;) [source] Pathways Among Marital Distress, Parental Symptomatology, and Child AdjustmentJOURNAL OF MARRIAGE AND FAMILY, Issue 2 2004Lauren M. Papp A community sample of 295 mothers, fathers, and children (M age = 11.14 years, SD = 2.32 years) rated marital distress, maternal and paternal psychological symptoms, and child adjustment. The predicted direct relations between these family and child variables were demonstrated for both fathers and mothers. Tests of pathways among these variables were conducted for separate but complementary mediation models. Maternal and paternal symptoms mediated the association between marital distress and child adjustment. Marital distress mediated the link between fathers' symptoms and child adjustment, but the direct pathway between mothers' symptoms and child adjustment remained. Pubertal status was modestly related to higher levels of family stressors. Joint implications of marital distress and parental symptoms for child adjustment are discussed. [source] Quantifying hepatic glycogen synthesis by direct and indirect pathways in rats under normal ad libitum feeding conditionsMAGNETIC RESONANCE IN MEDICINE, Issue 1 2009Ana F. Soares Abstract Hepatic glycogen synthesis from intact hexose (direct pathway) relative to that from gluconeogenic precursors (indirect pathway) was quantified in ad libitum-fed rats. Following 2H2O administration and overnight feeding, the livers were removed and glycogen 2H-enrichment was measured by 2H NMR. Six controls and six rats rendered hyperglycemic by streptozotocin (STZ; fasting blood glucose = 385 ± 31 mg/dl) were studied. The indirect pathway contribution, estimated as glycogen hydrogen 5 relative to hydrogen 2 enrichment, was 54% ± 4% for control rats,similar to values from healthy, meal-fed humans. In STZ-treated rats, the indirect pathway contribution was significantly higher (68% ± 4%, P < 0.05 vs. controls), similar to that of Type 1 diabetic (T1D) patients. In conclusion, sources of hepatic glycogen synthesis in rats during ad libitum nocturnal feeding were quantified by analysis of glycogen enrichment from 2H2O. STZ caused alterations resembling the pathophysiology of hepatic glycogen synthesis in T1D patients. Magn Reson Med 61:1,5, 2009. © 2008 Wiley-Liss, Inc. [source] Nondopaminergic mechanisms in levodopa-induced dyskinesiaMOVEMENT DISORDERS, Issue 8 2005Jonathan M. Brotchie PhD Abstract It has become increasingly apparent that Parkinson's disease involves many transmitter systems other than dopamine. This nondopaminergic involvement impacts on the generation of symptoms, on the neurodegenerative process, but, most tellingly, in the generation of side effects of current treatments, in particular, levodopa-induced dyskinesia (LID). Such mechanisms contribute not only to the expression of LID once it has been established but also to the mechanisms responsible for the development, or priming, of the dyskinetic state and the subsequent maintenance of the brain in that primed state. Within the basal ganglia, abnormalities in different nondopaminergic components of the circuitry have been defined in LID. In particular, a role for enhanced inhibition of basal ganglia outputs by the GABAergic direct pathway has been suggested as a basic mechanism generating LID. We speculate that the external globus pallidus and subthalamic nucleus may play distinct roles in different forms of dyskinesia, e.g., chorea/dystonia; peak/diphasic/off. At the cellular level, an appreciation of abnormal signaling by, among others, glutamatergic (NMDA and AMPA receptors in particular), ,2 adrenergic, serotonergic (5HT), cannabinoid and opioid mechanisms in both priming and expression of LID has begun to emerge over the last decade. This is being consolidated, though in many cases questions remain regarding the specific sites of such abnormality within the circuitry. Very recently, at the molecular level, mechanisms controlling neurotransmitter release and impacting on the ability of neurons to maintain particular forms of firing patterning and synchronization, e.g., SV2A, have been identified. This increased understanding has already delivered and will continue to define novel approaches to treatment that target both pre- and postsynaptic signaling molecules throughout the basal ganglia circuitry. © 2005 Movement Disorder Society [source] Ascending and descending brainstem neuronal activity during cystometry in decerebrate catsNEUROUROLOGY AND URODYNAMICS, Issue 4 2003Kimio Sugaya Abstract Aims This study was undertaken to examine the distribution of pontomedullary neurons related to micturition or urine storage, as well as the connections between the pontine micturition center (PMC), medullary neurons, and the spinal cord. Methods In decerebrate cats, extracellular recording of the rostral pontine and rostral medullary neurons was performed. Firing of each neuron was quantitated during cystometry. Connections between the PMC, medullary neurons, and the spinal cord (L1) were also examined electrophysiologically. Results Ninety-four neurons showed an increase or decrease of the firing rate during micturition. Units with an antidromic response to L1 stimulation and an increased firing rate were located in the nucleus locus coeruleus alpha (LCa; n,=,8) corresponding to the PMC, and in the medial reticular formation (MRF) of the medulla (n,=,14). Units showing a decreased firing rate were located in the nucleus reticularis pontis oralis (PoO; n,=,26) and in the MRF (n,=,11). The latencies of antidromic and orthodromic responses of the LCa units were longer than those of the PoO units. MRF neurons responded antidromically and/or orthodromically to stimulation of the PMC or L1. Conclusions These results suggest that the pathway concerned with urine storage has a faster spinobulbospinal loop than the micturition reflex pathway and that rostral medullary neurons also play an important role in micturition and urine storage. There may be two descending pathways between the PMC and the spinal cord: both a direct pathway and one by means of medullary neurons. Neurourol. Urodynam. 22:343,350, 2003. © 2003 Wiley-Liss, Inc. [source] Designed synthesis of nanostructured siloxane,organic hybrids from amphiphilic silicon-based precursorsTHE CHEMICAL RECORD, Issue 2 2006Atsushi Shimojima Abstract This paper reports on recent progress in the synthesis of nanostructured siloxane,organic hybrids based on the self-assembly of amphiphilic silicon-based precursors. A variety of ordered hybrid materials have been obtained by molecular design of the precursors. Alkoxysilanes and chlorosilanes with covalently attached hydrophobic organic tails are hydrolyzed to form amphiphilic molecules containing silanol groups, leading to the formation of layered (lamellar) structures. Transparent and oriented thin films of lamellar hybrids were prepared by the reaction in the presence of tetraalkoxysilane. In addition, the design of molecules having alkyl chains and large oligosiloxane heads led to the formation of mesophases consisting of cylindrical assemblies, providing a direct pathway to ordered porous silica. The synthesis, structural features, and formation processes of these hybrid mesostructures are discussed. © 2006 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 6: 53,63; 2006: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20073 [source] Differential Role of Naïve and Memory CD4+ T-Cell Subsets in Primary AlloresponsesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010D. Golshayan The T cell response to major histocompatibility complex (MHC) alloantigens occurs via two main pathways. The direct pathway involves the recognition of intact allogeneic MHC:peptide complexes on donor cells and provokes uniquely high frequencies of responsive T cells. The indirect response results from alloantigens being processed like any other protein antigen and presented as peptide by autologous antigen-presenting cells. The frequencies of T cells with indirect allospecificity are orders of magnitude lower and comparable to other peptide-specific responses. In this study, we explored the contributions of naïve and memory CD4+ T cells to these two pathways. Using an adoptive transfer and skin transplantation model we found that naive and memory CD4+ T cells, both naturally occurring and induced by sensitization with multiple third-party alloantigens, contributed equally to graft rejection when only the direct pathway was operative. In contrast, the indirect response was predominantly mediated by the naïve subset. Elimination of regulatory CD4+CD25+ T cells enabled memory cells to reject grafts through the indirect pathway, but at a much slower tempo than for naïve cells. These findings have implications for better targeting of immunosuppression to inhibit immediate and later forms of alloimmunity. [source] Indirect CD4+ TH1 Response, Antidonor Antibodies and Diffuse C4d Graft Deposits in Long-Term Recipients Conditioned by Donor Antigens PrimingAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009C. Ballet Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.Du molecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4+ indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibody-mediated rejection in human. [source] | |||||||||||||