Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a recent study, we demonstrated that vagal stimulation increases the survival of rats with myocardial infarction by inhibiting lethal arrhythmia through regulation of connexin43 (Cx43). However, the precise mechanisms for this effect remain to be elucidated. To investigate these mechanisms and the signal transduction for gap junction regulation, we investigated the effect of acetylcholine (ACh), a parasympathetic nerve system neurotransmitter, on the gap junction component Cx43 using H9c2 cells. When cells were subjected to hypoxia, the total Cx43 protein level was decreased. In contrast, pretreatment with ACh inhibited this effect. To investigate the signal transduction, cells were pretreated with L-NAME, a nitric oxide synthase inhibitor, followed by ACh and hypoxia. L-NAME was found to suppress the ACh effect. However, a NO donor, SNAP, partially inhibited the hypoxia-induced reduction in Cx43. To delineate the mechanisms of the decrease in Cx43 under hypoxia, cells were pretreated with MG132, a proteasome inhibitor. Proteasome inhibition produced a striking recovery of the decrease in the total Cx43 protein level under hypoxia. However, cotreatment with MG132 and ACh did not produce any further increase in the total Cx43 protein level. Functional studies using ACh or okadaic acid, a phosphatase inhibitor, revealed that both reagents inhibited the decrease in the dye transfer induced by hypoxia. These results suggest that ACh is responsible for restoring the decrease in the Cx43 protein level, resulting in functional activation of gap junctions.
 ...
PMID:Acetylcholine inhibits the hypoxia-induced reduction of connexin43 protein in rat cardiomyocytes. 1682 9

Neuroinflammation plays a role in the pathomechanism of many neurodegenerative diseases, including Parkinson disease (PD). Proteasome inhibition has also been known to be involved in the pathology of PD. Recent studies have reported that microglial activation and dopaminergic cell death were observed in in vivo lactacystin-induced models of PD. In the present study, we investigated whether proteasome inhibition had a direct effect on the inflammatory reaction. Lactacystin treatment increased the amount of nitric oxide and tumor necrosis factor alpha (TNF-alpha) in culture media containing murine microglia (BV-2). Neuronal cell death was more pronounced when the culture media containing BV-2 cells (BV-2 conditioned media; BV-2 CM) were harvested and treated with human dopaminergic neurons (SH-SY5Y) than when treated with lactacystin alone. Apoptosis was markedly increased by treatment with BV-2 CM, which could be mitigated by pretreatment with minocycline and N(omega)-nitro-l-arginine methyl ester (L-NAME). These results suggest that proteasome inhibition can directly trigger neuroinflammation, which leads to neuronal death.
 ...
PMID:BV-2 stimulation by lactacystin results in a strong inflammatory reaction and apoptotic neuronal death in SH-SY5Y cells. 1835 81

Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).
 ...
PMID:Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies. 3210 29