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Kun Wu

Publications and source records attributed to Kun Wu.

At least 19 recordsLinked to original sources
PubMed2026

Mechanisms underlying disease-causing variants in promoters and enhancers.

The study of human monogenic disorders has been a powerful tool for generating a deep understanding of protein function/dysfunction and for uncovering underlying biological mechanisms. Here we explore the insights that an expanding catalog of noncoding monogenic disease variants can provide into the functions of the noncoding genome. We focus on small genetic alterations (one to a few tens of base pairs) in cis-regulatory elements-promoters, enhancers and silencers-and their potential mechanisms of action, such as loss or gain of function. We discuss the challenges in determining pathogenicity for variants in the noncoding genome, discuss why there might be so few concrete examples and highlight the opportunities for advancing this area of human genetics by using experimental and machine-learning tools.

Journal Article↗
PubMed2007

Vitamin E analogs, a novel group of "mitocans," as anticancer agents: the importance of being redox-silent.

The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redox-silence is a prerequisite property for most of the anticancer activities described in this communication.

Animals↗
PubMed2006

alpha-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner.

Gastric neoplastic disease is one of the most frequent causes of cancer-associated deaths with poor prognosis. Here we studied the effect of the redox-silent analogue alpha-tocopheryl succinate (alpha-TOS), a strong apoptogen and anti-cancer agent, on the gastric cancer cell line SGC-7901. alpha-TOS inhibited proliferation of the cells and induced their apoptosis in a concentration- and time-dependent manner, while succinate or alpha-tocopherol showed no effect. The effect of alpha-TOS was modulated by components of the MAPK signaling network, including ERK1/2 and c-Jun N-terminal kinase (JNK), but not p38. Activation of ERK1/2 occurred early and increased until 12h, coinciding with an in crease in apoptosis in the cells, after which it dropped abruptly, while activation of JNK rose steadily, reaching a plateau at 12h of alpha-TOS treatment. The effects of ERK1/2 and JNK on the apoptosis outcome are transmitted via c-Jun, since transfection of the cells with c-Jun antisense oligodeoxynucleotide inhibited alpha-TOS-induced apoptosis. We conclude that ERK1/2 and JNK positively regulate apoptosis induced in gastric cancer cells by alpha-TOS.

Apoptosis↗
PubMed2006

Generation and weak beam control of two-dimensional multicolored arrays in a quadratic nonlinear medium.

We report on the first experimental observation of 2D multicolored transverse arrays in a quadratic nonlinear medium under the pump of two crossly overlapped femtosecond beams. The 2D reproducible patterns are caused by cascaded noncollinear quadratic nonlinear couplings between the input pulses and quadratic spatial solitons originated from spatial breakup of one of the input beams with spatial ellipticity. A seed supercontinuum pulse is then diffracted and amplified with phase preservation, resulting in the formation of up-converted multicolor 2D transverse arrays. By seeding with weak second harmonic pulses, the 2D multicolored transverse patterns are suppressed due to weak beam control of the induced quadratic spatial solitons.

Journal Article↗
PubMed2006

Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization.

Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.

Animals↗
PubMed2006

Novel technique for blood circuit reconstruction in mouse heart transplantation model.

PURPOSE: The surgical technique of heterotopic abdominal heart transplantation in mice, a standard model for transplantation immunology research, is very challenging restricting the widespread use of this model. A novel technique for the blood circuit reconstruction in heterotopic abdominal heart transplantation was developed. METHOD: The new method makes use of the suprahepatic inferior vena cava instead of the pulmonary artery of the donor heart for the anastomosis to the infrarenal vena cava of the recipient. FINDINGS: The sutures for the double vessel anastomoses were completed within 20.8+/-1.3 min, which was significantly shorter than 27.5+/-1.3 min in the traditional method. Similarly, the heart rebeating time postoperation (1.1+/-0.2 min) was significantly shortened as compared to 2.1+/-0.4 min using the traditional method. CONCLUSION: This novel technique facilitated abdominal heart transplantation in mice with reduced warm ischemia and grafted heart rebeating time.

Anastomosis, Surgical↗
PubMed2006

Vitamin E analogues as anticancer agents: lessons from studies with alpha-tocopheryl succinate.

The new millennium has witnessed considerable decrease in a number of previously fatal pathologies, largely due to the advancement in molecular medicine and modern approaches to treatment. In spite of this success, neoplastic disease remains a serious problem due to several reasons. These include an exceedingly high variability of cancer cells even within the same type of tumour. Cancer cells, albeit of clonal origin, mutate so that they escape established treatments, resulting in the fatal outcome of current therapies. Moreover, there are types of cancer, such as mesotheliomas, that cannot be treated at present. A novel group of clinically interesting anticancer drugs has been a recent focus in the literature that hold substantial promise as selective anticancer drugs. These compounds, epitomised by alpha-tocopheryl succinate, comprise redox-silent analogues of vitamin E that have been shown to suppress several types of cancer in animal models, including breast, colon and lung cancer as well as mesotheliomas and melanomas, while being nontoxic to normal cells and tissues. It is now proven that the strong anticancer effect of vitamin E analogues stems from their propensity to induce selective apoptosis in malignant cells. The results point to the novel group of vitamin E analogues as promising agents applicable to different types of tumours.

Animals↗
PubMed2006

[Analysis of postoperative complications of radical hysterectomy for 219 cervical cancer patients].

OBJECTIVE: To analyze the causes and therapeutic approaches for the complications of radical hysterectomy plus pelvic lymphadenectomy in cervical cancer patients. METHODS: From Jan. 1995 to Dec. 2003, 219 such patients were treated by radical hysterectomy plus pelvic lymphadenectomy. The stages were: 26 stage IA (17 stage IA1 and 9 stage IA2) (11.9%); 142 stage IB (78 stage IB1, 64 stage IB2) (64.8%); 40 stage IIA (18.3%) and 3 stage IIB (1.4%). 204 patients in this series were treated by radical hysterectomy plus pelvic lymphadenectomy and 15 by modified radical hysterectomy with pelvic lymphadenectomy. RESULTS: a total of 49 patients (22.4%) developed postoperative complications. The major complications included: bladder dysfunction (10.0%); formation of lymphocysts (7.8%); wound infection (6.8%); hydronephrosis (1.4%) and formation of ureteral fistulas (0.5%). The patients in the group treated by radical hysterectomy plus pelvic lymphadenectomy was likely to develop postoperative complication compared with the patients in the group by modified radical hysterectomy plus pelvic lymphadenectomy (24.0% versus 0, P = 0.067). The postoperative complication incidence in the patients who had preoperative neoadjuvant chemotherapy through intra-arterial catheter or radical radiotherapy in the other hospitals were 50.0% (2/4) and 100.0% (1/1), which were higher than that of the patients treated primarily in our hospital (21.3%, 25.3%) though without statistically significant difference among the groups. Of 52 patients who had previous abdominal surgery history, 13 developed posoperative complications, there was no significant difference between the patients with or without previous abdominal surgery history. The complication incidence of 87 patients treated with preoperative afterloaded radiotherapy was higher than that of 124 patients primarily treated by surgery (25.3% versus 19.4%), but the difference between two groups was statistically not significant (P = 0.239). CONCLUSION: The complication of radical hysterectomy with pelvic lymphadenectomy is correlated with the surgery mode. Preoperative afterloaded radiotherapy may not increase postoperative complication incidence. Properly reducing the extent of surgery may decrease incidence of complications.

Adolescent↗
PubMed2006

Effect of sulforaphane on cell growth, G(0)/G(1) phase cell progression and apoptosis in human bladder cancer T24 cells.

Isothiocyanates (ITCs) from cruciferous vegetables have been shown to be effective in blocking initiation as well as progression of a range of chemically-induced tumors in animal models. In this study, sulforaphane, the most extensively studied ITC, was found to suppress the growth of T24 bladder cancer cells in vitro in a dose-dependent manner. Sulforaphane inhibited the proliferation of T24 cells with IC(5)0 values 26.9 and 15.9 microM following 24 and 48 h treatments. Sulforaphane (5-20 microM) induced early apoptosis and blocked cell cycle progression at G(0)/G(1) phase which was associated with upregulation of cyclin-dependent kinase inhibitor p27 expression. These results support a role for sulforaphane as an effective agent in the chemoprevention of bladder cancer.

Anticarcinogenic Agents↗
PubMed2005

Inhibitory effects of apigenin on the growth of gastric carcinoma SGC-7901 cells.

AIM: To explore the growth inhibition and apoptosis-inducing effect of apigenin on human gastric carcinoma SGC-7901 cells. METHODS: The effects of apigenin on the growth, clone formation and proliferation of human gastric carcinoma SGC-7901 cells were observed by MTT, clone-forming assay, and morphological observation. Fluorescent staining and flow cytometry analysis were used to detect apoptosis of cells. RESULTS: Apigenin obviously inhibited the growth, clone formation and proliferation of SGC-7901 cells in a dose-dependent manner. Inhibition of growth was observed on d 1 at the concentration of 80 micromol/L, while after 4 d, the inhibition rate (IR) was 90%. The growth IRs at the concentration of 20, 40, and 80 micromol/L were 38%, 71%, and 99% respectively on the 7th d. After the cells were treated with apigenin for 48 h, the number of clone-forming in control, 20, 40, and 80 micromol/L groups was 217+/-16.9, 170+/-11.1 (P < 0.05), 98+/-11.1 (P < 0.05), and 25+/-3.5 (P < 0.05) respectively. Typical morphological changes of apoptosis was found by fluorescent staining. The cell nuclei had lost its smooth boundaries, chromatin was condensed, and cell nuclei were broken. Flow cytometry detected typical apoptosis peak. After the cells were treated with apigenin for 48 h, the apoptosis rates were 5.76%, 19.17%, and 29.30% respectively in 20, 40, and 80 micromol/L groups. CONCLUSION: Apigenin shows obvious inhibition on the growth and clone formation of SGC-7901 cells by inducing apoptosis.

Apigenin↗
PubMed2005

Cloning and expression of a novel isoform of heterogeneous nuclear ribonucleoprotein-R.

In the present study, we cloned a novel isoform of heterogeneous nuclear ribonucleoprotein-R (hnRNP-R), hnRNP-R2. Compared with the previously reported hnRNP-R (hnRNP-R1), it lacks the exon 5. Two proteins are both nuclear. The expression of hnRNP-R1 is not tissue-specific and is strikingly higher than that of hnRNR-R2. In comparison, the expression of hnRNP-R2 is low and neural-specific. The expression of two isoforms is differentially regulated during brain development. The results suggest that hnRNP-R may contribute to the regulation of neural development through the variation of hnRNP-R components in the hnRNP complex.

Amino Acid Sequence↗
PubMed2005

Tra2alpha promotes RA induced neural differentiation of P19 cells.

The present study demonstrates a high level of the nuclear Transformer 2alpha (Tra2alpha) protein in adult mouse brain relative to other tissues, including muscle, heart, liver, lungs, kidney and small intestine, suggesting the potential importance of Tra2alpha in neural function. The level of Tra2alpha in mouse cerebrum is developmentally regulated, peaking at neonate stage. In P19 carcinoma cells, Tra2alpha is transiently up-regulated upon retinoic acid (RA) treatment. Although over-expression of Tra2alpha protein alone does not elicit P19 differentiation, under these conditions the response of P19 cells to RA is significantly increased. The results suggest that Tra2alpha proteins may act as a mediator in the signal pathway associated with RA-induced differentiation in P19 cells.

Animals↗
PubMed2005

CD11b may be a less satisfactory indicator for cardiac ischemia-reperfusion injury in coronary artery bypass graft surgery with cardiopulmonary bypass than cardiac troponin I.

STUDY OBJECTIVE: To investigate whether CD11b on neutrophils can be used as a marker to predict myocardial ischemia-reperfusion injury for patients undergoing coronary artery bypass graft (CABG) surgery on cardiopulmonary bypass (CPB). DESIGN: Prospective, observational study. SETTING: University teaching hospital and university hospital laboratories. PATIENTS: Twelve adults, physical status II and III (American Society of Anesthesiologists) patients scheduled for elective CABG surgery on CPB. INTERVENTIONS: Anesthesia and surgical interventions were performed according to standard procedures. Coronary sinus was cannulated for retrograde cardioplegia perfusion and for coronary sinus blood sampling. The blood samples were collected from systemic and coronary venous sinus blood respectively at several time points before CPB, during CPB, and after declamping of the ascending aorta. MEASUREMENTS AND MAIN RESULTS: CD11b expressions in systemic circulation blood increased significantly during CPB and maintained higher levels after cardiac reperfusion (P < .05); on the other hand, CD11b expressions in coronary sinus blood declined gradually and reached their lowest level at 5 minutes after aortic declamping. The differences in CD11b expressions between systemic circulatory blood and coronary sinus blood after cardiac reperfusion were significant (P < .05). Cardiac troponin I (cTnI) concentrations in both systemic circulatory blood and coronary sinus blood increased significantly after cardiac reperfusion (P < .05), and the concentrations of cTnI in coronary sinus blood increased much higher than the corresponding concentrations of cTnI at each time point (P < .05). CONCLUSION: CD11b expression on neutrophils may not be a reliable predictor for myocardial ischemia-reperfusion injury in CABG surgery on CPB because of the possible sequestration of neutrophils in myocardium.

Adult↗
PubMed2005

[Preoperation risk factor analysis in orthotopic liver transplantation with pre-transplant artificial liver support therapy].

OBJECTIVES: Orthotopic liver transplantation (OLT) is an accepted therapy for selected patients with advanced liver diseases. However, the early mortality rate after OLT remains relatively high due to the poor selection of candidates with various serious conditions. The aim of this study is to assess the value of pretransplantation artificial liver support treatment in reducing the pre-operation risk factors relating to early mortality after OLT. METHODS: 50 adult patients in various stages of different etiologies who underwent OLT procedures had been treated with molecular adsorbent recycling system (MARS) preoperatively. The study was designed in two parts: the first one was to evaluate the effectiveness of a single MARS therapy by using some clinical and laboratory parameters which were supposed to be therapeutical pretransplantation risk factors. The second part was to study the patients undergoing OLT by using the regression analysis on preoperation risk factors relating to early (within 30 d after OLT) mortality rate. RESULTS: Among the 50 patients, a statistically significant improvement of the biochemical parameters was observed (pretreatment vs posttreatment). 8 patients cancelled their scheduled LTXs due to significant improvements in their clinical conditions or recovery of their failing liver functions. 8 patients died and 34 patients successfully underwent LTX. The immediate outcome (within 30 postoperative days) of these 34 patients was that 28 were kept alive and 6 died. CONCLUSIONS: Preoperation sequential organ failure assessment (SOFA), level of creatinine, INR, TNFalpha, and IL-10 are the main preoperative risk factors relating to early death after an operation. MARS treatment before a transplant operation can relieve these factors significantly, hence improve survival rate of liver transplantation or even make the transplantation unnecessary.

Aged↗
PubMed2005

[Roles of mitochondria in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells].

OBJECTIVE: In order to investigate the roles of mitochondria in vitamin E succinate (VES)-induced apoptosis in human gastric cancer SGC-7901 cells. METHODS: Mitochondrial transmembrane potential (deltapsi(m)) was observed by confocal laser scanning microscopy, while the expression of cytochrome c in cytosol and caspase-3 was measured by western blotting after the cells were treated with VES at 5, 10, 20 microg/ml. RESULTS: VES obviously decreased deltapsi(m) with dose- and time-dependent relationship, increased the expression of cytochrome c in cytosol and caspase-3 and activated caspase-3 as well. CONCLUSION: VES-induced apoptosis in SGC-7901 cells might involve mitochondrial permeability transition, release of cytochrome c and activation of caspase-3 downstream.

Apoptosis↗
PubMed2005

[Soluble expression and characterization of the immunoreactive multiepitope antigen of Toxoplasma gondii in E.coli].

OBJECTIVE: To obtain soluble expression product of immunoreactive recombinant multiepitope antigen of Toxoplasma gondii from E.coli. METHODS: The gene encoding the multiple epitopes (MEG) of Toxoplasma gondii was amplified by PCR from the original plasmid containing MEG gene and cloned into the prokaryotic soluble expression vector pET32a. After identification by enzyme digestion and sequencing, the positive recombinant plasmid pET32a-MEG was transformed into BL21(DE3), which was induced with IPTG for expression of the target antigen. The relative molecular mass, solubility and antigenicity of the expression products were analyzed by SDS-PAGE and Western blotting. RESULTS: The recombinant expression plasmid pET32a-MEG was successfully constructed and the highly efficient expression of the antigen was achieved after IPTG induction of E.coli. Improvement of the induction condition increased the expression product which accounted for about 28% of the total bacterial protein. The target protein, with good solubility and a relative molecular mass of about 31 000, was purified by immobilized metal affinity chromatography (Ni-NTA resin) and could be well recognized by mouse and rabbit antisera derived by infection of the animals with Toxoplasma gondii B36 and RH, respectively. CONCLUSION: The recombinant multiepitope antigen has good antigenicity and potential value in diagnosis and vaccine development of toxoplasmosis.

Animals↗