BACKGROUND: Mechanical allodynia is generally resulted from nerve damage by direct injury or inflammation. Thus, this study was designed to compare the antiallodynic effect of morphine, brimonidine and rilmenidine in two models of neuropathic pain, that is, induced by nerve ligation and neuritis. METHODS: Rats were prepared with tight ligation of the L5/L6 spinal nerves (SNL group) or with Freund's complete adjuvant (FCA) administration evoked sciatic inflammatory neuritis (SIN group). Antiallodynic effects by intrathecal morphine, brimonidine and rilmenidine were measured by applying von Frey filaments to the lesioned hind paw. Thresholds for withdrawal response were assessed and converted to % MPE to obtain an effective dose 50% (ED 50) and a dose response curve. RESULTS: Either SNL group or SIN group showed marked mechanical allodynia in the lesioned hind paw. Antiallodynic effects of morphine were different between two groups. That is ED 50 was 0.16 microgram (SIN) and 8.12 microgram (SNL), and dose response curve of the SIN group shifted left from that of the SNL group. The difference between SIN and SNL groups was statistically significant (P < 0.05). With the brimonidine or rilmenidine administration, ED 50 s were 0.12 microgram (SNL) and 0.37 microgram (SIN) and 2.16 microgram (SIN) and 11.46 microgram (SNL), respectively. And the shift to left of dose response curve from the SNL group is more prominent with rilmenidine administration. CONCLUSIONS: These results suggest morphine and rilmenidine showed a better effect on reducing the mechanical allodynia induced by FCA administration.
Animals ; Hyperalgesia ; Inflammation ; Ligation ; Morphine ; Neuralgia ; Neuritis ; Oxazoles ; Quinoxalines ; Rats ; Spinal Nerves ; Brimonidine Tartrate

AIMTo study the synthesis of 5-(3'-indolyl)-oxazoles and their antioxidative activity.

METHODSThe amides were prepared from tryptophan and different acid derivatives by the catalytic dehydration of dicyclohexyl carbodiimide (DCC). The characteristic heterocyclic ring system of 5-(3'-indolyl)-oxazoles was constructed by oxidative cyclization of amide, using dicholorodicyanoquinone (DDQ). Their antioxidative activity in vitro was tested using DPPH system.

RESULTSEleven 2-substituted phenyl-5-(3'-indolyl)-oxazoles were prepared, the compounds 21 and 22 have shown antioxidative activity 3-4 times stronger than that of Vit E, and the compound 29 showed antioxidative activity almost as same as Vit E.

CONCLUSIONThree 5-(3'-indoyl)-oxazole compounds synthesized showed potent antioxidative effect and they would be a good antioxidants.

Antioxidants ; chemical synthesis ; chemistry ; Indoles ; chemistry ; isolation & purification ; Molecular Structure ; Oxazoles ; chemistry ; isolation & purification

OBJECTIVE: Compared to elderly men, elderly women have substantially reduced performance of postural balance and greater risk of falls. To investigate the effect of age and sex on electromyographic (EMG) reaction time of tibialis anterior muscle contraction. METHOD: Fifty-nine elderly subjects and 29 young subjects participated in this study. Subjects were instructed to dorsiflex the ankle of the dominant leg as forcefully and quickly as possible in response to audible beeps. EMG activity was recorded over the tibialis anterior muscle and delays in initiation and termination of EMG signal were measured by two examiners. Mean and intrasubject variability of each delay were used as outcome measures. RESULTS: Both the intra-examiner and inter-examiner reliability of delay variables were above 0.97. Delays in initiation and termination of muscle contraction, as well as their intrasubject variability, were significantly greater in the elderly (p<0.01). However, there were no sex differences or interaction in all outcome measures. CONCLUSION: These results demonstrate that the EMG reaction time and their variability increase in the elderly population with no sex difference.
Aged ; Animals ; Ankle ; Electromyography ; Female ; Humans ; Leg ; Male ; Muscle Contraction ; Muscles ; Oxazoles ; Postural Balance ; Reaction Time ; Sex Characteristics

OBJECTIVETo investigate the effects of cycle-dependent kinase (CDK) inhibitor SNS-032 on apoptosis in human acute myeloid leukemia (AML) HL-60 cells and its molecular mechanisms.

METHODSCultured AML HL-60 cells were treated with various concentrations of SNS-032. Cell apoptosis was determined with flow cytometry;cell viability was measured by MTT assay; the profiles of microRNA expression of HL-60 cells were analyzed by microRNA microarray;the protein expressions of JAK2/STAT3 pathway were detected by Western blotting.

RESULTSApoptosis of AML HL-60 cells was induced by SNS-032; the rate of apoptosis was (5.9±1.7)%, (12.1±3.1)% and (59.4±3.6)% when HL-60 cells were treated with 0,100 and 200 nmol/L SNS-032. MicroRNA microarray analysis revealed that the levels of miR-30a, miR-183, miR-20b, miR-26b, miR-20a, miR-589, miR-107, miR-181a, miR-106a, miR-17 and miR-378c were down-regulated by SNS-032,whereas the levels of miR-320a and miR-H7* were up-regulated. Western blotting showed that SNS-032 strongly inhibited phosphorylation of STAT3 and protein expression of JAK2,C-MYC and MCL-1.

CONCLUSIONCDK inhibitor SNS-032 can induce apoptosis of AML HL-60 cells, which is associated with the inhibition of MCL-1,C-MYC and JAK2/STAT3, and down-regulation of miR-17-92 family.

Apoptosis ; Cell Survival ; Down-Regulation ; Flow Cytometry ; HL-60 Cells ; Humans ; Janus Kinase 2 ; metabolism ; MicroRNAs ; metabolism ; Oxazoles ; pharmacology ; Phosphorylation ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; Thiazoles ; pharmacology

BACKGROUND: Propofol is the extensively used general anesthetic-sedative agent.Although propofol is known to be involved in migration of various cells, migration response to it in vascular smooth muscle cells is not investigated. This study was carried out to determine the role of propofol in migration of rat aortic smooth muscle cells (RASMCs). METHODS: A7r5 RASMCs were used.Cell migration was examined by the analysis of 5 ng/ml of platelet-derived growth factor (PDGF)-induced RASMC response after treatment of cells with propofol (1-100micrometer) in the Boyden chamber.The activity of cofilin by propofol in RASMCs was measured by the Western blot analysis for the change of cofilin dephosphorylaton in cells treated with 10micrometer propofol for 5, 10, 15 and 20 min, for the effect of propofol (1, 10 and 100micrometer) on cofilin phosphorylation, and for the effects of ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetra acetic acid (2 mM; EGTA), Na3VO4 (200micrometer), and calyculin A (10 nM) on 10micrometer propofol-induced cofilin dephosphorylation. RESULTS: PDGF increased RASMC migration and this response was dose-dependently inhibited by treatment with propofol. Propofol attenuated the cofilin phosphorylation in RASMCs in a dose- and time-dependent manner.Propofol-induced dephosphorylation of cofilin in RASMCs was abolished by calyculin A, a protein phosphatase 2A inhibitor, but not by EGTA, a Ca2+ chelating agent, or Na3VO4, a protein tyrosine phosphatase inhibitor. CONCLUSIONS: The present results suggest that propofol induces the diminution of PDGF-stimulated RASMC migration and this response may be associated with dephosphorylation of cofilin mediated by the protein phosphatase 2A-dependent pathway.
Acetic Acid ; Animals ; Blotting, Western ; Egtazic Acid ; Emigration and Immigration ; Ethylenes ; Muscle, Smooth ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; Oxazoles ; Phosphorylation ; Platelet-Derived Growth Factor ; Propofol ; Protein Phosphatase 2 ; Protein Tyrosine Phosphatases ; Rats

OBJECTIVETo investigate the correlation between atorvastatin inhibiting the expression level of matrix metalloproteinase 9 (MMP-9) and peroxisome proliferator activated receptor alpha (PPARalpha) signal channel in myocyte of aging rat.

METHODSPrimary cultures of myocyte were got ten from aging rats. Myocyte were divided into control group, DMSO group, atorvastatin group, atorvastatin plus GW6471 group, which treated respectively by cell culture medium, DMSO, atorvastatin, atorvastatin plus GW6471. The expression of MMP-9 mRNA was evaluated by RT-PCR, and content of MMP-9 protein was detected by Western blot.

RESULTS(1) There was no difference between control group and DMSO group in level of MMP-9 mRNA and protein expression (P > 0.05); (2) The level of MMP-9 mRNA and MMP-9 protein expression in atorvastatin group were significantly lower than those in control group (P < 0.01); (3) Both level of MMP-9 mRNA and protein expression in atorvastatin plus GW6471 group were significantly higher than those in atorvastatin group (P < 0.05), but were still lower than those in control group (P < 0.05).

CONCLUSIONAtorvastatin inhibit MMP-9 expression of aging myocytes by PPARalpha signal channel.

Aging ; Animals ; Atorvastatin Calcium ; Cells, Cultured ; Heptanoic Acids ; pharmacology ; Matrix Metalloproteinase 9 ; metabolism ; Muscle Cells ; drug effects ; metabolism ; Oxazoles ; pharmacology ; PPAR alpha ; metabolism ; Pyrroles ; pharmacology ; Rats ; Rats, Wistar ; Signal Transduction ; Tyrosine ; analogs & derivatives ; pharmacology

Basing on the synthesis of pH-sensitive amphiphilic block copolymer poly (2-ethyl-2-oxazoline)-poly (D, L-lactide)(PEOz-PDLLA), this paper presents the preparation of docetaxel-loaded pH-sensitive block copolymer micelles using film dispersion method. The critical micelle concentration (CMC) was measured by pyrene fluorescent probe technique. The entrapment efficiency and drug-loaded amount were determined by HPLC. The morphology, diameter and surface potential of the micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential analyzer, respectively. The in vitro release behavior of DTX from polymeric micelles was investigated using dialysis method. The results indicated that the CMC, drug-loaded amount and entrapment efficiency of the micelles was 1.0 x 10(-3) g x L(-1), 15.0% and 91.1%, respectively. The micelles had a narrow size distribution, with a mean diameter of 28.7 nm. The micelle was globular-shaped and its zeta potential was (1.19 +/- 0.12) mV. In pH 7.4 PBS, docetaxel was released in a sustained manner from the micelles; while in PBS at pH 5.0, drug was released more rapidly, which suggested the pH-sensitive drug release behavior of the PEOz-PDLLA micelles. According to all the studies above, it can be concluded that the PEOz-PDLLA block copolymer micelles may be applied as promising drug delivery system for hydrophobic anti-tumor drugs.
Antineoplastic Agents ; administration & dosage ; metabolism ; Drug Carriers ; Drug Compounding ; Drug Delivery Systems ; Hydrogen-Ion Concentration ; Micelles ; Oxazoles ; chemistry ; Particle Size ; Polyamines ; Polyesters ; chemistry ; Polymers ; chemistry ; Taxoids ; administration & dosage ; metabolism

OBJECTIVETo investigate the antitumor efficacy and mechanism of HSP90 inhibitor FW-04-806 against Bcr/Abl(+) leukemia K562 and HL60 cells and their mechanisms of action.

METHODSMTT assay was used to assess the proliferation-inhibiting effect of FW-04-806. Cell cycle was analyzed with propidium iodide by flow cytometry. Cell apoptosis was determined using the FITC mV apoptosis detection kit. Western blot was applied to reveal the protein expression of related proliferative and apoptotic signaling pathways. The changes of mitochondrial membrane potential were detected by flow cytometry. Protein-protein interactions was shown by co-immunoprecipitation. The level of mRNA was assessed by real-time RT-PCR.

RESULTSFW-04-806 obviously inhibited cell proliferation in the HL60, K562 and HL60/Bcr-Abl cell lines, with an IC50 of (30.89 ± 0.12) µmol/L, (9.76 ± 0.19) µmol/L and (8.03 ± 0.26) µmol/L, respectively (P<0.001). Compared with the vehicle group, the two increasing doses of FW-04-806 showed inhibition of tumor growth at a rate of (17.40 ± 0.34)% and (34.33 ± 5.00)%, respectively, in the K562 cell line groups (P=0.003), and (18.90 ± 1.45)% and (35.60 ± 3.55)% (P=0.001) in the HL60/Bcr-Abl cell line groups. FW-04-806 dissociated Hsp90/Cdc37 chaperon/co-chaperon complex, followed by degradation of the Hsp90 proteins through proteasome pathway without affecting mRNA expression. FW-04-806 induced apoptosis and led to G2/M arrest.

CONCLUSIONOur findings indicate that FW-04-806 displays potential antitumor effect by suppressing the proliferation and apoptosis in Bcr/Abl(+) leukemia cells in vivo.

Apoptosis ; drug effects ; Cell Cycle ; Cell Proliferation ; drug effects ; Fusion Proteins, bcr-abl ; HL-60 Cells ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; Humans ; K562 Cells ; Leukemia ; drug therapy ; metabolism ; pathology ; Membrane Potential, Mitochondrial ; Oxazoles ; pharmacology ; RNA, Messenger ; metabolism ; Signal Transduction

OBJECTIVETo investigate the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) activation on transforming growth factor beta1 (TGF-beta1)-induced connective tissue growth factor (CTGF) expression in rat hepatic stellate cells (HSCs).

METHODSCultured HSCs with or without PPARgamma-specific antagonist GW9662 treatment prior to the addition of an increasing amount of PPARgamma natural ligand (15-d-PGJ2) or synthetic ligand (GW7845) were stimulated with TGF-beta1. The mRNA and protein levels of CTGF expression were detected by semi-quantitative RT-PCR and Western blotting, respectively. The morphological changes of the HSC were observed by electron microscope.

RESULTS15-d-PGJ2 and GW7845 significantly inhibited TGF-beta1-induced CTGF expression at both mRNA and protein levels in HSCs, and the inhibitory effect was dramatically, if not completely, abolished by pretreatment with GW9662, suggesting that the inhibition was mediated by PPARgamma. Morphological observation revealed that PPARgamma activation caused obvious changes of HSCs from activated to quiescent phenotypes.

CONCLUSIONPPARgamma ligand shows potent inhibitory effect on TGF-beta1-induced CTGF expression in rat HSCs, suggesting its potential as a candidate agent for treatment and prevention of hepatic fibrosis.

Animals ; Cells, Cultured ; Connective Tissue Growth Factor ; metabolism ; Hepatic Stellate Cells ; drug effects ; metabolism ; Oxazoles ; pharmacology ; PPAR gamma ; pharmacology ; RNA, Messenger ; genetics ; Rats ; Signal Transduction ; Transforming Growth Factor beta1 ; pharmacology ; Tyrosine ; analogs & derivatives ; pharmacology

This study was aimed to investigate the effect of SNS-032 (C17 H24 N4O2S2) on cell cycle, apoptosis, differentiation and self-renewal of hematopoietic stem cells (HSC) in mice. The self-renewal capability of bone marrow cells was measured by cobblestone forming cell test. The expressions of self-renewal regulation genes, cell cycle-related genes, apoptosis-related genes were measured by real-time PCR. The cell cycle status and apoptosis of HSC and HPC were detected by flow cytometry. The results showed that there was no significant difference of the frequency of HSC between SNS-032 and control group. The expressions of CDK1, CDK2, CDK7 and p27 decreased in HSC (P < 0.05) while the expressions of CDK4, CDK6, p21, p18, p19, Bcl-2, Bax, Puma, p53, Bim1, Sall4 and Notch1 showed no difference between SNS-032 group and control group (P > 0.05). The fraction of viable HSC in each phase of cell cycle remained unchanged after the treatment of SNS-032 (P > 0.05). Furthermore, there was no statistical difference in the apoptotic fractions between control and drug-treated groups (P > 0.05). It is concluded that SNS-032 induce apoptosis of cancer cells. Interestingly, SNS-032 has no significant inhibitory effect on self-renewal and differentiation of normal HSC, as well as no obvious effect inducing apoptosis of normal HSC and HPC.
Animals ; Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Cell Cycle ; drug effects ; Cell Cycle Proteins ; metabolism ; Cells, Cultured ; Hematopoietic Stem Cells ; cytology ; drug effects ; Mice ; Mice, Inbred C57BL ; Oxazoles ; pharmacology ; Thiazoles ; pharmacology