Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed ß,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

Effects of soybean isoflavones on the reproductive development of young mice / 中国药房

OBJECTIVE To investigate the effects of soybean isoflavones （SI） on the reproductive development of young mice. METHODS C57BL/6 young mice were randomly divided into control group， SI low-dose and high-dose groups （10， 100 mg/kg）， with 10 mice in each group （half male and half female）. The young mice in each group were given corresponding liquid intragastrically， once a day， for 2 consecutive weeks. After the last administration， the percentage of body weight increase was calculated； serum estradiol and testosterone levels， malondialdehyde （MDA） content， total antioxidant capacity （T-AOC）， superoxide dismutase （SOD） and glutathione peroxidase （GSH-Px） activities in the reproductive organs of the young mice were determined. The histopathological changes in the reproductive organs were observed. The cell apoptosis of reproductive organs was detected. RESULTS Compared with the control group， the percentage of body weight increase in female mice was increased significantly in the SI high-dose group， while that of male mice was decreased significantly （P＜0.05 or P＜0.01）. Cystic follicles could be seen in the ovarian tissue in SI groups， a loose arrangement of spermatocytes could be seen in the testicular tissue， and partial epithelial cell shedding could be seen in epididymal tissue. The serum level of testosterone in female young mice and the serum levels of testosterone and estradiol in male young mice in SI groups， GSH-Px activity in the ovarian tissue of female young mice in the SI low-dose group， T-AOC activities in the ovarian tissue of female young mice in SI groups as well as the apoptotic rates of cells in testicular and epididymal tissue of male young mice in SI groups were increased significantly （P＜0.05 or P＜ 0.01）； the serum level of estradiol in female young mice in SI groups， SOD activity in the ovarian tissue of female young mice in the SI high-dose group， and MDA contents in the ovarian tissue of female young mice in SI groups as well as the apoptotic rates of cells in ovarian tissue of female mice in SI groups were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS SI can enhance the antioxidant stress capacity of ovarian tissue in female young mice and reduce their oxidative stress damage， but it has certain toxicity to reproductive organs in male mice.

Clinical Observation on 24 Cases of Chronic Obstructive Pulmonary Disease of Stationary Phase Combined with Stable Angina Pectoris with Qi Deficiency-blood Stasis-phlegm Blockade Syndrome: Simultaneous Intervention for Heart and Lung / 中医杂志

Objective To examine the clinical effect of simultaneous intervention for heart and lung on chronic obstructive pulmonary disease (COPD) of stationary phase combined with stable angina pectoris with Qi deficiencyblood stasis-phlegm blockade syndrome.Methods Ninety-six COPD stationary phase combined with stable angina pectoris patients with Qi deficiency-blood stasis-phlegm blockade syndrome were randomized into control group,Juhong [Exocarpium Citri Rubrum] tablet group,the Tongxinluo (通心络) group and the Ju&Tong group,24 cases in each group.The control group was given western medicine routine therapy.In addition to the treatment of the control group,Juhong tablet 3.6 g was given to the Juhong tablet group orally,twice each day;Tongxinluo capsule 1.04 g was given to the Tongxinluo group orally,three times each day;Juhong tablet and Tongxinluo capsule were given to the Ju&Tong group.Each group was treated for 8 weeks.The following intems were compared before and after treatment including the scores of cough,cough up phlegm,dyspnea and St.George's Respiratory Questionnaire (SGRQ),anginal attacks,durante dolors,nitroglycerin consumption,pulmonary function [including forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)],as well as the levels of serum C reactive protein (CRP),interleukin 1β (IL-1β) and interleukin 10 (IL-10).Results After treatment,the scores of cough,cough up phlegm,dyspnea and SGRQ decreased in the Juhong tablet group,the Tongxinluo group and the Ju&Tong group.FEV1 and FVC increased.Anginal attacks,durante dolors,nitroglycerin consumption,as well as the levels of serum CRP,IL-1 βand IL-10 decreased.Moreover,the effect of certain indexes in the Ju&Tong group was superior to those in the Juhong tablet group and the Tongxinluo group (P ＜ 0.05 or P ＜ 0.01).Conclusion Simultaneous intervention for heart and lung might improve clinical symptoms and pulmonary function of COPD stationary phase combined with stable angina pectoris with Qi deficiency-blood stasis-phlegm blockade syndrome patients.Inhibiting chronic persistent inflammation might be one of the important mechanisms.

A serological biomarker in connective tissue disease-associated interstitial lung disease: Krebs von den lungen-6 / 中华风湿病学杂志

Objective To evaluate the serum Krebs von den Lungen (KL)-6 for the diagnosis of interstitial lung disease (ILD) associated with connective tissue diseases (CTD) and its lung-CT subtypes.Methods Seventy-five CTD patients were employed for this study,44 CTD with ILD and 31 ILD without ILD.The 44 CTD patients with ILD were further divided into different subgroups based on lung-CT imaging and clinical indexes.The enzyme-linked immune sorbent assay (ELISA) was used to measure the serum KL-6 level.For those data that was abnormally distributed,the differences between groups was compared with independent samples nonparametric tests.Results The level of serum KL-6 in the CTD with ILD was significantly higher than that without ILD [(1 118±877) U/ml vs (253±144) U/ml] (Z=-6.047,P＜0.01).By using a criterion of 500 U/ml,our data suggested that the serum KL-6 level was useful for the ILD-CTD diagnosis;the sensitivity,specificity,positive and negative predictive values were 72.7％,87.1％,88.9％ and 69.2％,respectively.The serum KL-6 level,however,showed no statistical differences between ILD subtypes,i.e.,usual interstitial pneumonia (UIP),nonspecific interstitial pneumonia (NSIP) and indeterminate [(1 104±843) U/ml,(1 242±1 039) U/ml,(815±400) U/ml,respectively] (x2=0.35,P=0.84).Our data further showed that the KL-6 level was significantly higher in CTD-ILD patients with intensive lung lesions than those with limited lung lesions [(1 910±918) U/ml vs (459±268) U/ml] (Z=-4.364,P＜0.01).In addition,the KL-6 level was significantly higher in active ILDs than in inactive ILDs[(1 478±917) U/ml vs (598±475) U/ml] (Z=-3.915,P＜0.01).Conclusion The serum KL-6 is a valuable biomarker for CTD-ILD diagnosis and even for the assessment of the extent and activity of lung damage.

Intra-articular injection of etanercept into the sacroiliac joint of ankylosing spondylitis / 中华风湿病学杂志

Objective To evaluated intra-articular injection of TNF-α inhibitors into the sacroiliac joint as an effective and viable alternative. Methods Sixteen patients with documented ankylosing spondylitis (AS), without steroids or disease modifying anti-rheumatic drugs (DMARDs) were performed CT-guided intra-articular injections of etanercept (TNF-α antagonist) at week 0, 4 and 8 (25 mg per dose). Similarly, 20 patients with AS in the control group received systemic etanercept therapy at a dose of 50 mg per week for 8 weeks. All patients were followed up clinically and evaluated periodically. Pathological features of sacroiliitis were observed with light microscopy and immunohistochemistry. Expression of cytokines in joint biopsy samples was estimated by RT-PCR. Image changes of sacroiliitis were observed by SPECT/CT and MRI. Ttest, t'tesr and χ2 Fisher's test were selected. Results All the 16 patients who received intra-articular etanercept, the mean value of radiological nuclide decrease of the SIJ ROI (region of interest) in the SPECT improved significantly after 8 weeks treatment [(1.38±0.16 vs 1.45±0.14) P<0.05] . Bone marrow edema and fat deposition in MRI were relieved significantly after 8 weeks (P<0.05). In 8 patients the expression of TNF-α and TGF-β mRNA in joint tissue decreased significantly after 8 weeks [(0.89±0.06, 0.84±0.05) vs (l.08± 0.19, 1.13±0.33) (P<0.05)]. The occurrence of gynonitis, enthesitis, chondritis, subehondral bony plate destruction, bone marrow inflammation and inflammatory cell index also decreased significantly (P<0.05). Participants given intra-articular injection showed significant clinical improvement after 8 weeks and 12 weeks treatment(P<0.01 ) in BASDAI score [(32±13) mm]. Conclusion This study has shown that intra-articular injection of etanercept in SIJ can improve joint function and quality of life. It has a satisfactory safety profile and is cost effective. This mode of treatment is most beneficial in local arthropathy of recent onset and in those patients who do not tolerate systemic etanercept therapy.

Reliability and correlation of in vivo heptic shimming of liver and water suppression with 3.0T proton MRS / 中国医学影像技术

Objective To assess the reliability of auto-shimming line width (LW) and water suppression rate (WS), and the correlation between them. Methods GE Signa Excite HD 3.0T system and eight-channel torso phased-array coils with PRESS sequence were performed in 38 volunteers. Liver spectra were collected with TR of 1500 ms, TE of 30 ms, VOI of 2 cm×2 cm×2 cm, NSA of 64 times. Spectroscopy routine auto-shimming pre-scanning program was executed and the values of LW and WS were recorded. Then another spectroscopy routine auto-shimming pre-scanning program was performed repeatedly and 38 groups of data were obtained totally. Intra-class correlation coefficients (ICC), coefficient of variation (CV) and significance test were conduced on 38 groups of LW and WS data. Spearman rank correlation analysis was used to assess the correlation of LW and WS. Results ①The ICC of LW and WS was 0.862 and 0.961 (both P＜0.0001), respectively, while the value of CV was 0.20, 0.18, 0.09 and 0.08, respectively. Significant difference was not observed; ②The value of correlation coefficient was -0.659, -0.485 (both P＜0.0001), respectively. Conclusion ①The reliability is excellent for in vivo liver 3.0T 1H-MRS and WS appears relatively stable; ②Indexes of LW correlate with WS moderately, and it seems the smaller the value of LW is, the easier to achieve higher WS.

Clinical and imaging findings in patients with severe acute respiratory syndrome / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the clinical and imaging characteristics of severe acute respiratory syndrome (SARS), and to study their relationship.</p><p><b>METHODS</b>Forty-six SARS confirmed patients were admitted to our hospital from February to April, 2003. X-ray examination documents were available in all cases and chest CT scanning was acquired in 6 cases, which were analyzed retrospectively, accompanied by their clinical features.</p><p><b>RESULTS</b>Fever was found in 97.8% of the patients. Clinical symptoms were mild, but X-ray and CT findings were distinct. CT scanning demonstrated ground glass like lesions and large patchy exudation and consolidation at the early stage in 6 cases. Different findings on radiography and CT were related to the different phases of the disease. After treatment, most lesions were absorbed completely, but slowly in patients with multi-lobe consolidation and/or extensive interstitial infiltration.</p><p><b>CONCLUSION</b>Special clinical and imaging findings could be found in SARS cases. The prognosis of SARS patients is related to the degree of lesions detected by radiography and CT.</p>

siRNA targeting STAT5 induces apoptosis in human hepatocellular carcinoma cell line SMMC-7721 / 第三军医大学学报

Objective To investigate the effects of inhibition of STAT5 gene expression by RNA interference technology on apoptosis of human hepatocellular carcinoma cell line SMMC-7721. Methods Three siRNA eukaryotic expression vectors against STAT5 were constructed and transfected with lipofectamineTM 2000 into SMMC-7721 cells. The changes in STAT5 expression were detected by semi-quantitative RT-PCR and Western blot. Cell apoptosis was assayed by flow cytometry (FCM). Results The sequence-specific siRNA could effectively and specifically inhibit STAT5 gene expression at both mRNA and protein levels. The inhibition rates of STAT5 mRNA expression were 70.43%, 43.02%, and 45.07%, respectively. The inhibition rates of STAT5 protein expression were 67.45%, 37.36%, and 41.86%, respectively. At 48 h after transfection, apoptosis rate was 25.61%. Conclusion siRNA against STAT5 can inhibit STAT5 gene expression in SMMC-7721 cells effectively and specifically and induce apoptosis of SMMC-7721 cells. siRNA targeting STAT5 has a great potential value in gene therapy of hepatocellular carcinoma.