As a tumor suppressor, p53 is activated by numerous cellular and environmental signals, and plays a criticalrole in the cell cycle regulation, cell apoptosis and senenscence. The murine double minute (MDM)2 and double minute mu?rine 4 (MDMX) are two important regulators. MDMX is a p53 binding protein with strong sequence homology to MDM2, but lacks ubiquitin ligase activity, and which is unable to target p53 for proteasomal degradation. MDMX regulates p53 activity through its binding with p53 and its postranscriptional modification. MDMX in the closed and open structure binds to p53 to regulate its activity. As the main partner of MDMX, casein kinase 1 alpha (CK1α) disrupts the intramolecular binding in MD?MX in the cooperation to regulate p53 activity. The process of MDMX and CK1αin the regulation of p53 is multi-step and complicated. In this paper the mechanism of MDMX and CK1αin the regulation of p53 protein was reviewed.

Allostasis ; physiology ; Chronic Disease ; General Adaptation Syndrome ; physiopathology ; Humans ; Stress, Psychological ; physiopathology

Acupuncture Therapy ; Aged ; Feeding and Eating Disorders ; therapy ; Humans ; Male

Acupuncture Therapy ; Adult ; Female ; Humans ; Laryngitis ; therapy

OBJECTIVETo investigate the effect of midazolam on human ether-a-go-go (hERG) K+ channels exogenously expressed in human embryonic kidney cells (HEK-293) and the underlying molecular mechanisms.

METHODSWhole-cell patch clamp technique was used to record WT, Y652A and F656C hERG K+ current expressed in HEK-293 cells.

RESULTSMidazolam inhibited hERG K+ current in a concentration-dependent manner, the half-maximum block concentrations (IC50) values were (1.31 ± 0.32) µmol/L. The half-activation voltage (V1/2) were (2.32 ± 0.38) mV for the control and (-1.96 ± 0.83) mV for 1.0 µmol/L midazolam. The half-inactivation voltage (V1/2) was slightly shifted towards negative voltages from (-49.25 ± 0.69) mV in control to (-57.53 ± 0.53) mV after 1.0 µmol/L midazolam (P < 0.05). Mutations in drug-binding sites (Y652A or F656C) of the hERG channel significantly attenuated the hERG current blockade by midazolam.

CONCLUSIONMidazolam can block hERG K+ channel and cause the speed of inactivation faster. Mutations in the drug-binding sites (Y652 or F656) of the hERG channel were found to attenuate hERG current blockage by midazolam.

Dose-Response Relationship, Drug ; Ether-A-Go-Go Potassium Channels ; drug effects ; HEK293 Cells ; Humans ; Midazolam ; pharmacology ; Mutation ; Patch-Clamp Techniques ; Potassium Channel Blockers ; pharmacology

Adult ; Aluminum Silicates ; toxicity ; Humans ; Middle Aged ; Mining ; Occupational Exposure ; Prevalence ; Silicosis ; epidemiology

ObjectiveTo explore the correlation between open field test(OFT) and light-dark box (LDB),as two animal models of state anxiety in Kunming mice.MethodsThe behavior of adult,male,Kunming mice in OFT and LDB was recorded by sequence,for five minutes,with a one-week inter-trial interval.The following parameters were evaluated:percentage of time exploring in the OFT central area( OFT-Ctime％ ) ; percentage of squares crossing in the OFT central area( OFT-Ccross％ ) ; total number of squares crossing in OFT(OFT-Cross) ;total number of rears in the OFT(OFT-Rear) ; number of fecal boli in OFT(OFT-FB) ; percentage of time exploring in the LDB light area( LDB-Ltime％ ) ; percentage of squares crossing in the LDB light area( LDB-Lcross％ ) ;and percentage of rears in the LDB light area( LDB-Lrear％ ) ; transitions between two areas in LDB( LDB-Transition) ; total number of squares crossing in LDB(LDB-Croas) ; total number of rears in LDB(LDB-Rear) ; number of fecal boli in LDB (LDB-FB).Subsequently,factor analysis,cluster analysis and correlation analysis were calculated for these parameters.ResultsFactor analysis and cluster analysis of variances from either OFT or LDB revealed a three behavioral dimensions:anxiety factor ( loaded by OFT-Ctime％,OFT-Ccross％ or LDB-Ltime％,LDB-Lcross％,LDB-Lrear％ ),activity factor ( loaded by OFT-Cross,OFT-Rear or LDB-Transition,LDB-Cross,LDB-Rear) and emotionality factor(loaded by OFT-FB or LDB-FB).While all the variances from both OFT and LDB in combination were analyzed,it could be seen as five components:' LDB-anxiety factor ( loaded by LDBLtime％,LDB-Lcross％ and LDB-Lrear％ ),' OFT-anxiety factor ( loaded by OFT-Ctime％ and OFT-Ccross％ ),'LDB-activity factor (loaded by LDB-Transition,LDB-Cross and LDB-Rear),'OFT-LDB-emotionality factor( loaded by OFT-FB and LDB-FB) and 'OFT-activity factor (loaded by OFT-Cross and OFT-Rear).Good correlation were found between OFT/LDB factors alone and in combination,such as OFT-emotionality factor and LDB-emotionality factor(Pearson =0.383,P＜0.05),LDB-anxiety factor and 'LDB-anxiety factor( Pearson =0.989,P＜0.01 ),OFT-anxiety factor and 'OFT-anxiety factor( Pearson =0.934,P ＜ 0.01 ),LDB-activity factor and 'LDB-activity factor ( Pearson =0.956,P ＜ 0.01 ),OFT/LDB-emotionality factor and ' OFT-LDB-emotionality factor ( Pearson =0.835,P＜0.01 ;Pearson =0.696,P＜0.01 ),OFT-activity factor and 'OFF-activity factor( Pearson =0.926,P＜0.01 ).ConclusionEither OFT or LDB comprised three behavioral dimensions:anxiety factor,activity factor and emotionality factor; however,it was difficult to establish face validity as a point-to-point concordance between OFT and LDB.Attention should be paid to heterogeneity of animal models when OFT and LDB were in combination as a behavionomics to evaluate anxiolytics in Kunming mice.

Objective To investigate the effect of valsartan,an angiotensinⅡtype 1 receptor (AT1 R)blocker,on radiosensitivity,invasive potential and proliferation activity of nasopharyngeal carcinoma cells(CNE-2)in vitro. Methods Radiosensitization of valsartan on CNE-2 cells in vitro was investigated by colony forming assay.Effect of ATl R blocker combined with radiation on invasive potential of CNE-2 cells was evaluated using 24-well Matrigel invasion chambers(Transwell).Apoptosis-inducing effect of valsartan combined with radiation on apoptosis of CNE-2 was identified by flowcytometry(FCM). Resuits When valsartan was given at 10-9.10-8 and 10-7 mol/L combined with radiation,sensitivity enhancement ratios (SER)were 1.10,1.20 and 1.36.and the invasive inhibition rates were 8.11%,16.49%and 16.77%,respectively.The SER of valsartan on CNE-2 distinctly increased when the exposure time was increased.After 24 h exposure to 10-8 mol/L valsartan combined witIl radiation.the apoptosis rate was 1.89%±0.09%,which was higher than 1.62%±0.06%in radiation alone group(t=4.79.P＜0.05). Conclusions AT1 R blocker valsartan combined with radiation can significantly inhibit the proliferation activity of nasophar,cngeal carcinoma cells in vitro in a dose- and time-dependent manner.Valsartan combined with radiation can potently inhibit the invasive potential of CNE-2.which may be involved in the mechanism of valsartan treatment in vivo.

BACKGROUND:Impaired balance between osteogenesis and adipogenesis of bone marrow mesenchymal stem cels is a crucial pathological mechanism of osteoporosis. Mechanical loads applied to bone tissue can increase bone formation and improve bone strength, and meanwhile lead to the release of extracelular nucleotides, such as adenosine triphosphate.
OBJECTIVE: To determine the effects of adenosine triphosphate on the osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cels and to investigate the underlying mechanisms.
METHODS:The effect of adenosine triphosphate (10, 50, 250 μmol/L) on differentiation of bone marrow mesenchymal stem cels were measured by osteogenic and adipogenic related genes expression, alizarin red staining and oil red O staining. The activation of ERK1/2 signaling pathway by adenosine triphosphate was tested using western blot assay.
RESULTS AND CONCLUSION: Incubation of bone marrow mesenchymal stem cels with adenosine triphosphate resulted in the dose-dependent increase of osteogenic genes expression and calcium deposition, and inhibition of adipogenic genes expression and lipid droplet formation, but had no effects on cel proliferation. Adenosine triphosphate activated ERK1/2 signaling pathway, and U0126 as an ERK1/2 inhibitor restrained the effect of adenosine triphosphate on the differentiation of bone marrow mesenchymal stem cels.

This study was aimed to elucidate the 5-HT3R molecular mechanism of Radix Paeoniae Albaextract (RPAE) as drug intervention in the treatment of premenstrual syndrome (PMS) model rats with liver-qi depression pattern.PMS model rats with liver-qi depression pattern were prepared.And then,the model was treated with RPAE.The protein distribution of 5-HT3AR and 5-HT3BR in the frontal lobe was evaluated by the immune fluorescence technology and western blot.The results showed that there were positive expressions of 5-HT3AR and 5-HT3BR in frontal lobe of rats in each group.Compared with the normal group,the 5-HT3AR and 5-HT3BR protein expression levels of the frontal lobe in the model group increased significantly (P < 0.05).Compared with the model group,the 5-HT3AR protein expression level in the frontal lobe decreased significantly after RPAE treatment (P < 0.05).In conclusion,RPAE regulated the protein expressions of 5-HT3AR and 5-HT3BR in frontal lobe,which may be one of the mechanisms for its treatment of PMS with liver-qi depression pattern.