1.Targeting androgen receptor and trail: a novel treatment paradigm for breast cancer
TU YA-PING ; XIE YAN ; ABEL W PETER ; WEI TAO-TAO ; LUO XU
Chinese Journal of Pharmacology and Toxicology 2017;31(10):954-954
OBJECTIVE TNF- related apoptosis- inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors. However, most breast cancer cells are resistant to TRAIL- induced apoptosis. Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance. METHODS To identify modulators of TRAIL-induced apoptosis, we carried out a genome wide siRNA screen. To validate the screening result, we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model. Finally, we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy. RESULTS We unexpectedly identified androgen receptor (AR) to be responsible for TRAIL resistance. While AR is classically viewed as the key factor in prostate cancer progression, we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple- negative breast cancers (TNBC) that are highly aggressive with poor prognosis. Importantly, breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance. AR overexpression in MDA- MB- 231 and MDA- MB- 436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis. AR overexpression also induced TRAIL resistance in breast tumors in vivo. Further, we observed an upregulation of the TRAIL receptor, death receptor 5 (DR5) in breast cancer cells, following the removal or inhibition of AR by its antagonists Casodex and MDV3100. Treatment with AR antagonists also enhanced TRAIL- induced breast cancer cell apoptosis. CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis, in part, by suppressing DR5 expression, and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.
2.Impact of Age and Vascular Endothelial Function on Arterial Stiffness in Isolated Systolic Hypertersion
Ya-Li WU ; Meng-Jue LEI ; Qiu-Ling LIU ; Yan-Ping TU ; Ai-Bin GONG ;
Chinese Journal of Hypertension 2006;0(08):-
Objective To investigate the impact of aging and vascular endothelial function on arterial stiff- ness in patients with isolated systolic hypertension.Methods Patients with isolated systolic hypertension (ISH,n=75)age-matched healthy subjects(n=30)and young healthy subjects(n=50)were submitted to deter- mination of aortic pulse wave velocity(baPWV)and vascular endothelial function evaluated by flow-mediated dila- tion(FMD).Results baPWV was progresively decreased(ISH:2459.2?436.8 vs elderly healthy:2097.2? 315.7 vs young healthy:1619.7?214.2 cm/s,P
3.Neurotransmitter systems in mouse airways
ABEL W PETER ; KIEFFER M CAMERON ; TU YA-PING
Chinese Journal of Pharmacology and Toxicology 2017;31(10):1015-1016
OBJECTIVE The objective of this study was to characterize the neurotransmitter systems that cause constriction of murine airways. METHODS Murine precision cut lung slices (PCLS) and trachea were prepared, placed into perfusion chambers equipped with platinum electrodes and stimulated transmurally (1.0 ms, 50 V, 0.1- 30 Hz). To measure PCLS constriction, changes in airway luminal area in response to electric field stimulation (EFS) were captured as video images quantified using Image J software. For trachea, changes in isometric tension were recorded using Grass force transducers. Frequency response curves were generated in the absence and the presence of the inhibitors magnesium, atropine and capsaicin and responses analyzed and compared using a student' s t- test (P<0.05). RESULTS EFS caused airway constriction in a frequency-dependent manner that was best fit by a biphasic curve. Neuron-specific stimulation was verified by Mg2+ blockade. Maximum airway constriction to 30 Hz EFS in PCLS was (51.8±3.0)% while tracheal constriction averaged (551±80)mg. Interestingly, in PCLS the muscarinic receptor antagonist atropine (10 μmol · L- 1) blocked (99.5 ± 7.2)% of EFS induced constriction at 1 Hz, but only blocked (23.3±3.8)% of EFS induced constriction at 30 Hz and eliminated the first phase but not the second phase of the biphasic EFS response. Treatment with capsaicin to deplete sensory neurotransmitters significantly increased EFS constriction supporting the presence of sensory neurotransmitter systems in airways. CONCLUSION These data are consistent with parasympathetic constriction of airways by acetylcholine at lower EFS frequencies while higher frequencies release sensory dilator neurotransmitters. These data provide evidence for multiple nerve types innervating airways which may provide novel targets for treatment of lung disease.
4.Simultaneous determination of flavones and saponins of Rhizoma Anemarrhenae by HPLC-DAD-ELSD.
Xiao-Nan SU ; De JI ; Ya-Ping ZHOU ; Li-Jun WANG ; Wen-Yi ZANG ; Chun-Qin MAO ; Tu-Lin LU
China Journal of Chinese Materia Medica 2015;40(1):108-111
This study is to establish an HPLC-DAD-ELSD method for simultaneous determination of 5 flavones and saponins in Rhizoma Anemarrhenae including neo-mangiferin, mangiferin, timosaponin B II, timosaponin B III and timosaponin A III. Samples were analyzed on a Merck Purospher STAR column(4.6 mm x 250 mm, 5 μm). The mobile phase consisted of acetonitrile( A) and 0. 1% formic acid (B) with gradient elution at a flow rate of 1.0 mL · min(-1). The column temperature was set at 40 °C. The DAD detector wavelength was set at 254 nm. The ELSD conditions were as follows: the nebulizing gas flow rate was 2.0 L · min(-1) and temperature of drift tube was 105 °C. The volume was 10 μL. The five compounds were well separated with good linear correlations. The mean recoveries were between 102.0%-104.0%. This method was quick and reliable which provides a foundation for quality control of R. Anemarrhenae.
Anemarrhena
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chemistry
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Chromatography, High Pressure Liquid
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instrumentation
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methods
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Drugs, Chinese Herbal
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analysis
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Flavones
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analysis
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Rhizome
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chemistry
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Saponins
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analysis
5.Effect of Telbivudine Tablet Combined Jianpi Bushen Recipe on HBV Specific Cytotoxic T Lymphocyte and HBeAg Seroconversion in Patients with HBeAg Positive Chronic Hepatitis B.
Zhong HUA ; Wei XU ; De-cai FU ; Yi-guang LI ; Xiao-ye GUO ; Kang-wan TU ; Ya-ping DAI
Chinese Journal of Integrated Traditional and Western Medicine 2016;36(5):530-534
OBJECTIVETo explore the effect of Telbivudine (LDT) Tablet combined with Jianpi Bushen Recipe (JBR) on serum hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) and HBeAg seroconversion in chronic hepatitis B (CHB) patients.
METHODSTotally 90 HBeAg-positive and human leukocyte antigen (HLA)-A2 positive CHB patients were randomly assigned to the treatment group and the control group, 45 cases in each group. Patients in the treatment group took LDT Tablet (600 mg, once per day) combined with JBR granule (twice per day), while those in the control group took LDT Tablet alone. The therapeutic course for all was one year. HBV DNA negative conversion rate, HBeAg seroconversion rate, and level of HBV specific CTL were compared after 1 year treatment; liver function, drug resistance mutations, and adverse reactions were also compared between the two groups.
RESULTSAfter 1 year treatment, HBV DNA negative conversion rate and HBeAg seroconversion rate were 88.89% (40/45) and 40.00% (18/45) in the treatment group, higher than those of the control group [68.89% (31/45) and 20.00% (9/45)], with statistical difference (P < 0.05). Level of HBV specific CTL in the treatment group was 0.78% +/- 0.09% after treatment, higher than that of the control group after 1 year treatment (0.54% +/- 0.11%) and that before treatment (0.36% +/- 0.07%), with statistical difference (P < 0.01). Level of HBV specific CTL in 27 patients with HBeAg seroconversion was 0.81% 0.10%, higher than that of 63 patients without HBeAg seroconversion (0.60% +/- 0.09%), with statistical difference (P < 0.01). ALT returned to normal in 44 cases of the treatment group (97.78%), while it was 42 cases (93.33%) of the control group, with no statistical difference between the two groups (P > 0.05). Total bilirubin (TBil) in the two groups all turned to normal. rtM204I variation occurred in 1 case (2.22%) of the treatment group and 2 cases (4.44%) in the control group. No obvious adverse reaction occurred in the two groups.
CONCLUSIONLDT Tablet combined with JBR could elevate levels of HBV specific CTL and HBeAg seroconversion in CHB patients.
Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; Hepatitis B, Chronic ; drug therapy ; Humans ; Seroconversion ; T-Lymphocytes, Cytotoxic ; immunology ; Tablets ; Thymidine ; analogs & derivatives ; therapeutic use
6.Expression of USP15, TβR-I and Smad7 in psoriasis.
Ai-Ping, FENG ; Yi-Min, HE ; Xin-Xin, LIU ; Jia-Wen, LI ; Ya-Ting, TU ; Feng, HU ; Shan-Juan, CHEN
Journal of Huazhong University of Science and Technology (Medical Sciences) 2014;34(3):415-9
The deubiquitinating enzyme ubiquitin specific peptidase 15 (USP15) is regarded as a regulator of TGFβ signaling pathway. This process depends on Smad7, the inhibitory factor of the TGFβ signal, and type I TGFβ receptor (TβR-I), one of the receptors of TGFβ. The expression level of USP15 seems to play vital roles in the pathogenesis of many neoplasms, but so far there has been no report about USP15 in psoriasis. In this study, immunohistochemical staining of USP15, TβR-I and Smad7 was performed in 30 paraffin-embedded psoriasis specimens and 10 normal specimens to investigate the expression of USP15, TβR-I and Smad7 in psoriasis and to explore the relevance among them. And USP15 small interfering RNA (USP15 siRNA) was used to transfect Hacat cells to detect the mRNA expression of TβR-I and Smad7. Of 30 cases of psoriasis in active stage, 28, 24 and 26 cases were positive for USP15, TβR-I and Smad7 staining, respectively. The positive rates of USP15 and Smad7 were significantly higher in psoriasis specimens than in normal skin specimens (44.1%±26.0% vs. 6.1%±6.6%, 47.2%±27.1% vs. 6.6%±7.1%), and positive rate of TβR-I (20.3%±22.2%) in psoriasis was lower than that in normal skin specimens (46.7%±18.2%). There was a significant positive correlation between USP15 and Smad7 expression, and significant negative correlations between USP15 and TβR-expression, an I d between TβR- and Smad7 expression I in psoriasis. After transfection of USP15 siRNA in Hacat cells, the expression of TβR-mRNA was up I -regulated and that of Smad7 was down-regulated. It is concluded that USP15 may play a role in the pathogenesis of psoriasis through regulating the TβR-I/Smad7 pathway and there may be other cell signaling pathways interacting with USP15 to take part in the development of psoriasis.
7.Analysis of Th1/Th2 response pattern for erythrodermic psoriasis.
Ping, ZHANG ; Hong-Xiang, CHEN ; Yi-Qun, DUAN ; Wei-Zhen, WANG ; Tian-Zhu, ZHANG ; Jia-Wen, LI ; Ya-Ting, TU
Journal of Huazhong University of Science and Technology (Medical Sciences) 2014;34(4):596-601
As one of the most serious types of psoriasis, pathogenesis of erythrodermic psoriasis (EP) is unclear so far. In this study, we aimed to detect the levels of Th1/Th2 cytokine-associated transcription factors and T-lymphocyte clone in peripheral blood mononuclear cells (PBMCs) derived from EP patients, and gene expression level of T-bet/GATA-3 in skin lesion. The potential role of Th1/Th2 reaction pattern played in the pathogenesis of EP was also discussed. Serum levels of IFN-γ, IL-2, IL-4 and IL-10 were quantified by ELISA among 16 EP patients, 20 psoriasis vulgaris (PV) patients and 15 healthy controls. The expression levels of T-bet/GATA-3 in the skin lesion and PBMCs were examined by real-time qPCR. The ratio of Th1/Th2 was measured by flow cytometry. The levels of IFN-γ, IL-2, IL-4 and IL-10 were higher in EP patients than in the healthy controls. The levels of IL-4 and IL-10 were 69.44±11.45 and 12.62±4.57 pg/mL, respectively, in EP patients, significantly higher than those in PV patients and healthy controls (P<0.05). Flow cytometry revealed the levels of both Th1 and Th2 in PBMCs from EP patients were higher than those in healthy controls, and the Th1/Th2 ratio was dramatically lower than in PV patients (P<0.01). The ratios of IFN-γ/IL-4 and T-bet/GATA-3 in EP patients were both less than 1.0, suggesting a reversal when compared with the other two groups. Our study indicated that the EP patients exerted a Th1/Th2 bidirectional response pattern, and the balance of Th cell subsets inclines to Th2, which might be one of the important mechanisms of EP pathogenesis.
8.Study on electroacupuncture treatment of depression by magnetic resonance imaging.
Dong-mei DUAN ; Ya TU ; Li-ping CHEN ; Zheng-jun WU
Chinese Acupuncture & Moxibustion 2009;29(2):139-144
OBJECTIVETo explore the changes of metabolites in brain after treatment by analysis on 1H-MRS examination of the hippocampus and prefrontal lobe in the healthy volunteers and the depression patients.
METHODSSeventy-five cases of mild and moderate depression were randomly divided into groups A, B and C, 25 cases in each group. The group A was treated with oral administration of Prozac capsule, 20 mg/d; the group B by electroacupuncture for 30-40 min and the needle was retained for 1 h, once each day, with main points Baihui (GV 20), Yin-tang (GV 29) and adjuvant acupoints selected; the group C by combination of the treatment methods in the groups A and B. They were treated for 6 weeks. Use PROBE-J sequence at the MRI system on Single Voxel of ROI of each lateral of hippocampus and frontal lobe in the depression patients of the 3 groups. Compare the differences of N-acetylasp artate/creatine (NAA/Cr) and choline/creatine (Cho/Cr) between the healthy volunteers and the patients before and after treatment.
RESULTSBefore treatment, NAA/Cr in the bilateral hippocampus decreased in the 3 groups as compared with the control group, and after treatment, NAA/Cr in the bilateral hippocampus of the group B and in the right hippocampus of the group C increased compared with that before treatment (P < 0.05), and NAA/Cr in the left hippocampus of the group C significantly increased as compared with that before treatment (P < 0.01). Before treatment, Cho/Cr in the bilateral prefrontal lobe in the 3 groups increased as compared with that in the control group (P < 0.05), after treatment, Cho/Cr in the bilateral prefrontal lobes of the groups A, B and C significantly decreased as compared with that before treatment (P < 0.05, P < 0.01).
CONCLUSIONThere are differences in contents of metabolites in corresponding parts in bilateral frontal lobes and hippocampus between the depression patient and healthy person.
Adult ; Choline ; metabolism ; Creatine ; metabolism ; Depression ; diagnostic imaging ; metabolism ; therapy ; Electroacupuncture ; Female ; Frontal Lobe ; diagnostic imaging ; metabolism ; Hippocampus ; diagnostic imaging ; metabolism ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Radiography ; Young Adult
9.Assessment of effectiveness of electroacupuncture and fluoxetine for treatment of depression with physical symptoms.
Dong-mei DUAN ; Ya TU ; Li-ping CHEN
Chinese Acupuncture & Moxibustion 2008;28(3):167-170
OBJECTIVETo study on clinical therapeutic effect and safety of electroacupuncture and Fluoxetine for treatment of mild or moderate depression with physical symptoms.
METHODSSeventy-five cases were randomly divided into a western medicine group (group A), an electroacupunctue group(group B) and an electroacupuncture plus medicine group (group C), 25 cases in each group. The group A were treated by oral Fluoxetine, 20 mg each day; the group B by electroacupuncture with Baihui (GV 20) and Yintang (EX-HN 3) selected as main points; the group C by oral administration of Fluoxetine plus electroacupunctue. HAMD depression scale was used for assessment of clinical therapeutic effect and TESS adverse reaction scale was used for adverse reactions.
RESULTSThe clinical effective rate was 78.3% in the group A, 82.6% in the group B and 91.7% in the group C, with significant differences between group C and A, group C and B (P < 0.05). Groups B and C had significant therapeutic effects in improvement of physical symptoms, and the adverse reaction of Fluoxetine in the group C was less than that in the group A.
CONCLUSIONElectroacupuncture can significantly improve physical symptoms and relieve adverse reactions of Fluoxetine. Electroacupuncture combined with Fluoxetine has a better therapeutic effect on depression with mild or moderate physical symptoms, with less adverse reactions.
Adult ; Antidepressive Agents, Second-Generation ; therapeutic use ; Combined Modality Therapy ; Depression ; therapy ; Electroacupuncture ; Female ; Fluoxetine ; therapeutic use ; Humans ; Male ; Middle Aged
10.The role of endogenous opioid peptides in paraventricular nucleus of hypothalamus in the antagonism to myocardial ischemia by electroacupuncture at acupoint "Neiguan" (PC 6).
Hua WANG ; Qian TU ; Ya-Wen WANG ; You-Xiang LIU ; Xu-Ping WU
Chinese Acupuncture & Moxibustion 2005;25(10):720-724
OBJECTIVETo explore the mechanism of electroacupuncture at "Neiguan" (PC 6) antagonizing myocardial ischemia injury.
METHODSForty rabbits were randomly divided into 4 groups, model control group, naloxone control group, electroacupuncture plus cerebral spinal fluid group, and electroacupuncture plus naloxone group, 10 rabbits in each group. The effects of electroacupuncture at "Neiguan" (PC 6) after injection of naloxone into the paraventricular nucleus (PVN) of the hypothalamus on myocardial ultrastructure, II lead ECG and transmembrane potentials of the ischemic myocardial cell in the rabbit of myocardial ischemia were investigated.
RESULTSThe injection of naloxone into PVN has no effect on myocardial functions in the normal rabbit and a little effect on ischemic myocardial functions, but at 60 min after myocardial ischemia, this has a certain protective action on myocardial functions (P < 0.05); electroacupuncture at "Neiguan" has obvious protective action on ischemic myocardium, which can be reduced by injection of naloxone into PVN (P < 0.05), but can not be blocked.
CONCLUSION(1) PVN plays an important role in the process of antagonizing myocardial ischemia by electroacupuncture at "Neiguan"; (2) endogenous opioid pepetides in PVN are involved in the acupuncture effect of antagonizing myocardial ischemia; (3) other transmitters in PVN and other nucleus groups in the center also can produce obvious effects in the antagonism to myocardial ischemia by electroacupuncture at "Neiguan".
Acupuncture Points ; Animals ; Electroacupuncture ; Humans ; Myocardial Ischemia ; Opioid Peptides ; Paraventricular Hypothalamic Nucleus