| Objectives: To investigate the expression of glucocorticoid receptor(GR) α, β, γ, P and serine/arginine-rich protein (SRp)30c,40in patientswith systemic lupus erythematosus (SLE), to explore the differential ex-pression of GR isoforms in GC resistant patients, and to determine whetherSRp30c and SRp40could regulate the expression of GR isoforms.Methods:70patients (female/male,65/5; median age was42) withSLE and38healthy controls (female/male,35/3; median age was40)serving as age and gender matched controls were included in this study.Enrollment took place between October2009and June2012in the FirstAffiliated Hospital of Dalian Medical University. The patients were di-vided into low activity group (32cases; female/male,29/3; median age was41.5) and high activity group (38cases; female/male,36/2; median agewas43) when they were enrolled in hospital.All the patients took prednisone (0.5-1mg/kg/day orally) as part oftheir routine therapy for4weeks. After the treatment for four weeks, thepatients were classified into two groups according to their response toprednisone: steroid-sensitive (SS) group (56cases; female/male,52/4;median age was46) and SR group (14cases; female/male,13/1; medianage was40).Four different GR transcripts and SRp30c, SRp40mRNA in peripheralblood mononuclear cells (PBMCs) were examined by Semi-quantitative re-verse transcriptase-polymerase chain reaction (RT-PCR). Trial registrationwas ChiCTR-RCH-12002808.Results: The mRNA expression of four isoforms showed the follow- ing trend in controls: GRα>GRγ>GRP>GRβ. The percentages of GRα, β, γ,P expression of the total GR in SLE patients were66.20%、19.37%、14.20%、0.23%, respectively. The mRNA expression of four isoformsshowed the following trend in SLE patients: GRα>GRP>GRγ>GRβ. Thepercentages of GRα, β, γ, P expression of the total GR in SLE patientswere59.88%、26.06%、14.02%、0.04%, respectively. GRβ mRNA ex-pression in SLE patients was significantly lower (0.68×10-2v4.10×10-2,P=0.002), while GRP expression was significantly higher (4.64v2.56,P=0.004). GRα and SRp40expression in SR group were significantlylower than that in SS group (8.79v17.34, P=0.050;55.55v72.29,P=0.039, respectively). GRγ expression showed no significant differencebetween any two groups. In addition, there was significant negative cor-relation between SLEDAI score and GRα (r=-0.289, P=0.021), and positivecorrelation between expression of SRp40and GRα in SLE group (r=0.444,P<0.001).Conclusions: GRα was the predominant GR isoform that mediates GCresponce. Decreased expression of GRα might predict the activity of illnessand imply one of the molecular mechanisms of SR in patients with SLE. Inaddition, SRp40could upregulate GRα transcript in PBMCs of SLE patients,which may become a potential treatment target to improve GC responce. Objective: To examine whether amifostine could protect patients withmultiple myeloma (MM) from Bortezomib-induced peripheral neuropathy(BiPN) while maintaining the therapeutic efficacy, and to explore theunderlying mechanism of amifostine protecting peripheral nerve.Methods: Schwann cells (SCs) were pretreated with amifostine (0,0.5,1,2, or4mM) in vitro for30min before exposure to400nMbortezomib, respectively. Cell viability, reactive oxygen species (ROS)levels, aggresome formation, and chaperone-mediated autophagy (CMA)activation were examined. Forty-seven patients with MM were recruitedfrom the First Affiliated Hospital of Dalian Medical University betweenJune2011and November2012. Bortezomib was administered i.v. at a doseof1.0mg/m2on days1,4,8, and11in combination with20–40mg/d of i.v.dexamethasone on days1–4and8–11in one21–day cycle and100mg/d ofp.o. thalidomide during treatment. Patients were randomized to receive4–6cycles of a VDT regimen with/without pretreatment with amifostine (400mg)30min before bortezomib therapy. The incidence and severity of BiPNwere assessed before and after treatment using the National Cancer InstituteCommon Terminology Criteria for Adverse Events (NCI-CTCAE, version2.0). Trial registration: ChiCTR-TCC-12002759Results: In vitro, the IC50concentration of bortezomib was400nMfor RSC-96cells. The viability of cells in group C2was significantly higherthan that in group B (79.16±0.64vs.51.06±1.14, P <0.05). ROS levelswere lower in cells in group C2than in group B (22.43±1.31vs.63.63±2.14, P <0.05). And pretreatment with amifostine for30min significantlyreduced the percentage of cells forming aggregates (73.54±1.87vs.41.1±8.4, P <0.05). In addition, amifostine induced cytoplasmic chaperone andCMA receptor expression at lysosomal membranes and autophagosomeformation at different stages. Amifostine therapy had no effect on completeresponse rates (34.78%vs.37.5%, P>0.05). The incidence of BiPN was lower in patients receiving amifostine (62.5%vs.78.26%), although notsignificantly (P>0.05). The incidence of grade3–4NCI was significantly(P <0.05) lower in those who received amifostine (8.33%vs.39.13%).Conclusions: Amifostine appears to be a promising prophylactic agentthat acts against BiPN by reducing ROS generation and aggresomeformation via CMA activation. |
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