Spectroscopic and computational exploration of hypoxanthine riboside interacting with plasma albumin.

Hypoxanthine riboside (HXR) is a nucleoside essential for wobble base pairs to translate the genetic code. In this work, an absorption and luminescence study showed that HXR and human serum albumin (HSA) formed a new complex through hydrogen bonds and van der Waals forces at ground state. Fluorescence probe experiments indicated that HXR entered the first subdomain of domain II in HSA and was fixed by amino acid residues in site I defined by Sudlow, and after competing with a known site marker. The recognition interaction featured negative ΔHÏ´ , ΔSÏ´ and ΔGÏ´ thermodynamic parameters. Fluorescence and circular dichroism spectra described the polarity of residues and α-helix and ß-strand content changed because of HXR binding. The most rational structure for the HXR-HSA complex was recommended by the molecular docking method, in which the binding location, molecular orientation, adjacent amino acid residues, and hydrogen bonds were included. In addition, the influence of ß-cyclodextrin and some essential metal ions on the balance of the HSA-HXR system interaction was measured. The study gained comprehensive information on the transportation mechanism for HXR in blood, and was of great significance in understanding the theory of HXR biotransformation and in discussing its clinical in vivo half-life.

Study on the molecular recognition action of lamivudine by human serum albumin.

In this work, the interaction of an anti-HIV drug lamivudine and human serum albumin (HSA) was studied by multispectroscopic and molecular modeling methods. The fluorescence emission spectra showed that the fluorescence of HSA was quenched by lamivudine through static mechanism with HSA-lamivudine complex produced at ground state. According to the binding equilibriums observed at 4 different temperatures, the number of binding site, binding constant, enthalpy change, entropy change, and Gibbs free energy change of the interaction were calculated. The results indicated that there was only 1 main binding site under present concentration condition, and then, the location of this binding site was ascertained by molecular probe experiments using warfarin and ibuprofen as site markers. The interaction was a spontaneous and exothermic process. Hydrogen bonds and van der Waals force were the major power that fixed lamivudine on Sudlow's site I in subdomain IIA of HSA molecule. The distance between donor and acceptor was determined by Förster's nonradiative fluorescence resonance energy transfer theory. Circular dichroism spectra exhibited the alteration of HSA's secondary structures. Molecular modeling investigation revealed the structure of HSA-lamivudine complex, including the conformation of lamivudine in binding site, the amino residues close to lamivudine, and the interaction forces between receptor and ligand. The study may be beneficial to therapists in understanding the distribution of lamivudine in vivo and explaining its drug-resistant mechanism in clinical diagnosis.

Role of Beclin 1-dependent autophagy in cardioprotection of ischemic preconditioning.

Emerging evidence indicates that ischemic preconditioning (IPC) induces autophagy which attenuates myocardial ischemia/reperfusion (I/R) injury. However, the precise mechanisms remain complex and unclear. The present study was to investigate which autophagy pathway was involved in the cardioprotection induced by IPC, so that we can acquire an attractive treatment way for ischemic heart disease. Adult male Sprague-Dawley (SD) rats were randomly divided into sham group, I/R group and IPC group. IPC was induced with three cycles of 5 min regional ischemia alternating with 5 min reperfusion in a heart I/R model. Samples were taken from the center of the infracted heart and examined by using the electron microscopy, the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method, Western blotting and co-immunoprecipitation (Co-IP). A large number of autophagic vacuoles were observed in the cardiomyocytes of IPC group as compared with I/R group. LC3-II formation, an autophagy marker, was up-regulated in IPC group as compared with I/R group (P<0.05). Moreover, the interaction between Beclin 1 and Bcl-2 was significantly increased in IPC group as compared with I/R group (P<0.01). It was also found that IPC decreased I/R-induced apoptosis (P<0.01). These results suggest that IPC inhibits Beclin 1-dependent excessive autophagy in reperfusion phase and cooperates with anti-apoptosis pathway to diminish the cell death induced by the myocardial I/R injury.

Effect of carbamylation on the molecular recognition action of amino benzothiazole by carrier protein.

Increasing benzothiazole derivatives containing amino or N-acyl structures in position 2 have been largely developed as pesticides and medicines. However, the structure-function relationship of 2-substituted benzothiazole derivatives has seldom been illustrated from the perspective of their albumin-binding nature. Herein, to probe the influence of carbamylation on the albumin-binding nature of benzothiazole derivatives, formyl group was introduced to the amine group of 2-amino benzothiazole (ABT) to yield a novel modified ABT (MABT). Their protein-binding properties were systematically deciphered by spectroscopy, molecular modeling and density functional theory (DFT) calculations. The interaction mechanisms, recognition thermodynamics and binding geometry were investigated and compared. The structural alteration of human serum albumin was explored using synchronous fluorescence emission and circular dichroism spectrum technologies. Based on experimental results, the structures of protein complex with MABT and ABT were revealed by molecular docking method. The differences in energy transfer efficiency and molecular orientation of ABT and MABT in new complexes were tentatively explained by DFT calculations. The work was expected to help to understand the impact of different substituents on the bioactivity of benzothiazole derivatives and guide for structural designs of new compounds.

Comprehensive analysis of the effect of rs2295080 and rs2536 polymorphisms within the mTOR gene on cancer risk.

There is still no conclusion on the potential effect of the rs2295080 and rs2536 polymorphisms of mTOR (mammalian target of rapamycin) gene on different cancers. Herein, we performed a comprehensive assessment using pooled analysis, FPRP (false-positive report probability), TSA (trial sequential analysis), and eQTL (expression quantitative trait loci) analysis. Eighteen high-quality articles from China were enrolled. The pooled analysis of rs2295080 with 9502 cases and 10,965 controls showed a decreased risk of urinary system tumors and specific prostate cancers [TG vs. TT, TG+GG vs. TT and G vs. T; P<0.05, OR (odds ratio) <1]. FPRP and TSA data further confirmed these results. There was an increased risk of leukemia [G vs. T, GG vs. TT, and GG vs. TT+TG genotypes; P<0.05, OR>1]. The eQTL data showed a potential correlation between the rs2295080 and mTOR expression in whole blood samples. Nevertheless, FPRP and TSA data suggested that more evidence is required to confirm the potential role of rs2295080 in leukemia risk. The pooled analysis of rs2536 (6653 cases and 7025 controls) showed a significant association in the subgroup of "population-based" control source via the allele, heterozygote, dominant, and carrier comparisons (P<0.05, OR>1). In conclusion, the TG genotype of mTOR rs2295080 may be linked to reduced susceptibility to urinary system tumors or specific prostate cancers in Chinese patients. The currently data do not strongly support a role of rs2295080 in leukemia susceptibility. Large sample sizes are needed to confirm the potential role of rs2536 in more types of cancer.

Long-term liver cancer incidence and mortality trends in the Changning District of Shanghai, China.

OBJECTIVE: To evaluate the trends and estimate the long-term effects of age, period and birth cohort on the incidence and mortality rates of liver cancer (LC) in an urban district of Shanghai, China. METHODS: Crude and age-standardized rates of the incidence and mortality of LC were calculated from 1973 to 2013 annually by sex, and the direction and magnitude of the trends were estimated by the average annual percentage change (AAPC) using the Joinpoint Regression Model. An age-period-cohort (APC) model was also used to evaluate the non-linear effects of calendar time and birth cohort on LC incidence and mortality. RESULTS: In 1973-1977 and 2008-2013 the age-standardized rates of LC incidence and mortality (per 100 000) were 24.27 and 22.60 in men, and 7.50 and 7.26 in women, respectively. Declining trends of LC incidence and mortality rates were observed for both sexes (AAPC; P < 0.05 for both). The APC models indicated that the rates of LC incidence and mortality were significantly influenced both by calendar time and birth cohort effects. CONCLUSIONS: The incidence and mortality rates of LC have decreased in both sexes in the Changning District of Shanghai over the past four decades. Although obvious descending trends of LC incidence and mortality were detected, attention should also be paid to the LC burden for a long time in the future because of huge population size in China and the continuity of population aging.

Pharmacological effects of serum containing chinese medicine Bushen Huayu Jiedu Compound Recipe in lung cancer drug-resistance cells.

OBJECTIVE: To explore the pharmacologic effects of Chinese medicine Bushen Huayu Jiedu Compound Recipe (BSHYJDR) in drug-resistance cells of lung cancer. METHODS: Human lung adenocarcinoma A549/DDP cell strain was selected, serum pharmacology and flow cytometer (FCM) method were adopted, S180 tumor-bearing mice and normal mice were given, through gastrogavage, different doses of a decocted concentration of BSHYJDR. Serum from the abdominal aorta was taken to observe the effect of drug-serum on cisplatin (DDP) concentration, free Ca2+ concentration and the expression of lung drug-resistance protein LRP-56 in A549/DDP cells. RESULTS: Compared with the drug-resistance group, the intracellular DDP concentration in the group taking a high dose and the normal group of Chinese medicine showed significant difference (P<0.05), while no significant difference was found in the low-dose group (P>0.05). Compared with the drug-resistance group, the Ca2+ concentration in cells and the expression of LRP in lung cancer drug-resistance cells A549/DDP of the high-dose group, the low-dose group and the normal group of Chinese medicine were significantly different (all P<0.01), the LRP expression of the normal group was obviously higher than that of the drug-resistance group (P<0.05). CONCLUSION: It was indicated that serum containing Chinese medicine BSHYJDR in the tumor-bearing mice and the normal mice had certainly different, tumor-bearing mice serum containing could improve drug concentration in lung cancer drug-resistance cells, prevent the inflow and release of Ca2+, and inhibit the expression of the drug-resistance gene in the lung cancer drug-resistance cells, which might be the mechanism of BSHYJDR in enhancing the efficacy in reversing and inhibiting tumor.

Time trends of incidence and mortality in colorectal cancer in Changning District, Shanghai, 1975-2013.

OBJECTIVE: To evaluate the incidence and mortality of colorectal cancer (CRC) and the estimated patient's age, diagnostic duration and birth cohort effects in patients of Changning District, Shanghai. METHODS: Age-standardized rates (ASRs) of CRC over eight intervals of 5 years from 1975 to 2013 were determined. Joinpoint regression analysis was used to determine the changes in annual incidence and mortality trends. Age-period-cohort analysis was performed to investigate their effects on the incidence and mortality trends of CRC. RESULTS: For incidence, the ASRs of 14.14 per 100 000 and 11.81 per 100 000 during 1975-1979 increased to 32.11 per 100 000 and 26.25 per 100 000 in men and women during 2008-2013. For mortality, ASRs of 9.40 per 100 000 and 8.76 per 100 000 increased to 14.80 per 100 000 and 11.92 per 100 000 in men and women, respectively, from 1975-1979 to 2010-2013. Joinpoint regression analysis found an increasing incidence (average annual percentage change [AAPC] 2.18% for men and 1.65% for women) and mortality (AAPC 1.47% for men and 0.97% for women) of CRC throughout the entire period. The incidence and mortality trends of CRC were significantly affected by birth cohorts. CONCLUSIONS: The increasing incidence and mortality of CRC are largely affected by the effects of birth cohorts. The increased incidence of CRC may be attributed to changes in lifestyle and diet, while that in mortality trends may be resulted from increasing incidence, an aging population and changing lifestyles.

Antitumor and synergistic effect of Chinese medicine "bushen huayu jiedu recipe" and chemotherapy on transplanted animal hepatocarcinoma.

AIM: To investigate the antitumor and synergistic effect of Chinese medicine "bushen huayu jiedu recipe" (recipe for invigorating the kidney, removing blood stasis and toxic substances) and chemotherapy on mice hepatocarcinoma. METHODS: Bushen huayu jiedu recipe (BSHYJDR) consisting of Chinese Cassia Bark, Psoralea, Zedoary, Rhubarb, etc. is equal to 1.5 g/mL liquid of originated herbs after being decocted, filtered, and concentrated. Kunming mice, weighing 18-22 g, were injected with 0.2 mL ascitic hepatocarcinoma H22 containing 1x10(7) cells/mL into armpit of the right forelimb of mice. After 24 h, the mice were weighed and randomly divided into tumor-bearing model control group, cisplatin (DDP) group, BSHYJDR high dosage group, low dosage BSHYJDR group, DDP combined with high and low dosage BSHYJDR group, 10 mice in each group. DDP group received injection intraperitoneally (i.p.) at the dosage of 1 mg/kg (equal to 1/10 LD50), once a day for 4 d. High and low dosage BSHYJDR groups received intragastric BSHYJDR at the dosages of 26.6 and 13.3 g/kg (20 and 10 times each of clinical adult dosage) respectively, while tumor-bearing model group received the equal volume of distilled water once a day for 10 d. On the 11th d, the mice were weighed and killed, then the tumor was dissected and weighed, the repression rate (RR) was calculated according to the mean weight of tumor (MWT). RESULTS: Compared to the model group (MWT: 1.30+/-0.73), DDP group (MWT: 0.41+/-0.09, RR: 68.46%) had a significant difference in the inhibition of hepatocarcinoma H22 (P<0.01). High dosage BSHYJDR group (MWT: 0.69+/-0.29, RR: 46.92%) also had a significant difference in inhibition (P<0.05), while no difference was found in low dosage BSHYJDR group (MWT: 0.85+/-0.34, RR: 34.62%) (P>0.05). When DDP was combined with high dosage BSHYJDR (MWT: 0.29+/-0.17, RR: 77.69%) and low dosage BSHYJDR (MWT: 0.38+/-0.21, RR: 70.77%) respectively, we could see improvement of the inhibition effect of DDP on transplanted hepatocarcinoma H22. DDP combined with high dosage BSHYJDR had a significant difference (P<0.001) compared to DDP, while DDP combined with low dosage BSHYJDR only had a little improvement that is not remarkable. CONCLUSION: Chinese medicine BSHYJDR in combination with chemotherapy can inhibit transplanted hepatocarcinoma in mice.

[Transperitoneal laparoscopic enucleation of renal angiomyolipoma: a report of 10 cases].

OBJECTIVE: To evaluate the feasibility and clinical effect of transperitoneal laparoscopic enucleation of renal angiomyolipoma (RAML) without obstruction of renal pedicle. METHODS: Ten patients with renal angioleiomyoma (tumor diameter < 4 cm) were operated by transperitoneal laparoscopy without obstruction of renal pedicle. The operating time, blood loss, hospital stay after operation, intraoperative and postoperative complications and the operative effect were observed. RESULTS: All the 10 patients underwent the operation successfully. The average operating time was 90 min, average blood loss was 80 ml, the average hospital stay after operation was 7 d. No intraoperative or postoperative complications occurred. Follow-up period was 3-19 months and no tumor metastasized or occurred again. CONCLUSION: This mininvasive procedure is a more precise and complete method than before, which can minimize the blood loss and make patients recover quickly, so it is well worth clinical applying.

Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients.

OBJECTIVE: Professional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs). METHODS: We searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect. RESULTS: Twelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3(+) T-lymphocytes (MD=-11.65, P<0.05) and CD4(+) T-lymphocytes (MD=-8.18, P<0.01) of the combination group were higher. CONCLUSIONS: Immunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.

The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence.

BACKGROUND: Although a previous meta-analysis reported no association between metabolic syndrome (MetS) and prostate cancer risk, a number of studies suggest that MetS may be associated with the aggressiveness and progression of prostate cancer. However, these results have been inconsistent. This systematic review and meta-analysis investigated the nature of this association. METHODS: We systematically searched MEDLINE, EMBASE and bibliographies of retrieved studies up to January 2013 using the keywords "metabolic syndrome" and "prostate cancer". We assessed relative risks (RRs) of the prostate cancer, several parameters of prostate cancer aggressiveness and progression associated with MetS using 95% confidence intervals (95% CIs). RESULTS: The literature search produced 547 hits from which 19 papers were extracted for the meta-analysis. In cancer-free population with and without MetS, the combined adjusted RR (95% CI) of prostate cancer risk and prostate cancer-specific mortality in longitudinal cohort studies is 0.96 (0.85 ~ 1.09) and 1.12 (1.02 ~ 1.23) respectively. In the prostate cancer patients with and without MetS, the combined unadjusted OR (95% CI) of high grade Gleason prostate cancer is 1.44 (1.20 ~ 1.72), the OR of advanced prostate cancer is 1.37 (1.12 ~ 1.68) and the OR of biochemical recurrence is 2.06 (1.43 ~ 2.96). CONCLUSIONS: The overall analyses revealed no association between MetS and prostate cancer risk, although men with MetS appear more likely to have high-grade prostate cancer and more advanced disease, were at greater risk of progression after radical prostatectomy and were more likely to suffer prostate cancer-specific death. Further primary studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required.

Assessment of tamsulosin as a potential male contraceptive in healthy volunteers.

OBJECTIVE: To investigate the efficacy and safety of tamsulosin, an α(1A)-adrenoceptor antagonist, as a potential male contraceptive. METHODS: Forty healthy male volunteers were equally divided into 2 groups, each of which received placebo and tamsulosin sequentially in a crossover manner. Ejaculatory profile was examined 4 to 6 hours after administration and adverse effects were noted. RESULTS: Anejaculation occurred in all subjects after taking 0.8-mg of tamsulosin. Total functional sperm count was significantly reduced in subjects after taking 0.4-mg of tamsulosin. Six subjects receiving 0.8-mg of tamsulosin complained of tolerated discomfort, which disappeared 10 hours after administration. CONCLUSION: When administered at 0.8 mg, tamsulosin can cause anejaculation with some transient side effects. Our results imply that tamsulosin and related drugs might potentially be used as male contraceptive agents in the future, which needs more studies to verify.

Comparison of tamsulosin with extracorporeal shock wave lithotripsy in treating distal ureteral stones.

BACKGROUND: Tamsulosin, an alpha-1 receptor antagonist, has been demonstrated effective in promoting distal ureteral stone passage and in reducing pain associated with stone expulsion. This study aimed to evaluate the effect of tamsulosin in comparison with nifedipine and extracorporeal shock wave lithotripsy (ESWL) on the expulsion rate of distal ureteral stones at different sizes. METHODS: We assigned 314 patients to three categories: I, the stone with maximal diameter of 4.0 - 5.9 mm; II, 6.0 - 7.9 mm, and III, 8.0 - 9.9 mm. Patients in each category were randomly subdivided into three treatment subgroups: group A (nifedipine group), group B (tamsulosin group), and group C (ESWL group). Stone-free rate and the dose of analgesics were recorded weekly during the 4-week follow-up period. RESULTS: Three hundred and three patients completed the study. The results showed that nifedipine and tamsulosin treatments promoted a small (4 - 8 mm, categories I and II) stone expulsive rate that was comparable with ESWL treatment. Nonetheless, when the stone diameter was 8.0 - 9.9 mm, ESWL showed a greater stone free rate than nifedipine and tamsulosin treatments; no significant difference existed between the latter two therapies. Although the ESWL treatment group required the least analgesics, tamsulosin treatments required less pain medication than nifedipine (P < 0.05). CONCLUSIONS: Tamsulosin treatment is recommended for patients with the stone diameter smaller than 8 mm because of its feasibility, effectiveness and safety. ESWL is more appropriate than tamsulosin therapy for the patients whose stones are larger than 8 mm.