Comparative Study on Neutron Irradiation Sensitization Effects of Nucleotide Borate Esters and Several Other Boron Agents.

More effective boron-containing compounds are needed for use in boron neutron capture therapy (BNCT). Here, borate esters were synthesized by heating and dehydrating nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), the nucleoside (inosine) or glycerol in the presence of boric acid (H3BO3). Borate ester products were compared to clinical boron agent boronophenylalanine (BPA) and several other borate esters for neutron-sensitization effects using the A549 cell line. Cells were incubated with boron agent solutions (2.3 mM) for 5 h, then washed, resuspended in fresh media, and irradiated with a neutron dose of 0.33 Sv followed by cell survival assessment using the CCK-8 method. Calculated radiosensitization values (control group cell survival rate/boron agent-treated experimental group cell survival rate) were 3.9 ± 0.2 (ATP borate ester), 2.4 ± 0.1 (BPA), 2.1 ± 0.1 (ADP borate ester), 1.9 ± 0.2 (AMP borate ester), 1.7 ± 0.3 (glycerin borate ester), 1.4 ± 0.1 (inosine borate ester), 1.3 ± 0.3 (triethanolamine borate ester) and 1.3 ± 0.5 (H3BO3). Borate esters derived from nucleotides ATP, ADP or AMP exhibited significantly higher sensitization values than did those derived from glycerol, inosine or triethanolamine. Notably, due to its relatively higher water solubility and degree of tumor cell enrichment, ATP borate ester exhibited the highest sensitization rate overall, significantly exceeding rates obtained for BPA and borate esters of ADP and AMP. Flow cytometric determinations of boron agent-treated cell survival at 24 h postirradiation revealed long-term apoptosis rates of 4.8-6.6 ± 0.2% (nucleotide borate ester groups) and 5.6 ± 0.3% (BPA group) compared to 3.9 ± 0.1% (irradiation control group without boron agent) and 2.6 ± 0.2% (blank control group). Significant differences between experimental and control groups demonstrated that nucleotide borate esters and BPA induced long-term radiosensitization effects. In particular, postirradiation percentages of ATP borate ester-treated cells progressing to DNA replication prophase (G1 phase) increased significantly, while percentages of cells progressing to S phase significantly decreased, demonstrating cellular DNA replication inhibition. Meanwhile, boron content values of tumor tissue, measured using inductively coupled plasma mass spectrometry (ICP-MS) and expressed as tumor-to-normal tissue boron ratios (T/N), were not significantly different between nucleotide borate ester- and BPA-fed groups of tumor-bearing mice. However, tumor tissue boron concentrations of nucleotide borate ester-fed mice (0.81-0.88 ± 0.04 µg/g) significantly exceeded those of BPA-fed mice (0.52 ± 0.05 µg/g) and thus provided greater tumor tissue boron enrichment for achieving a stronger neutron radiation-sensitizing effect. In conclusion, nucleotide borate esters, especially ATP borate ester, exhibited superior neutron radiosensitization effects than did other representative borate ester compounds and significantly greater long-term radiation effects as well. Thus, nucleotide borate esters have several advantages over other borate esters for BNCT and therefore warrant further study.

A novel EGFR-TKI inhibitor (cAMP-H3BO3complex) combined with thermal therapy is a promising strategy to improve lung cancer treatment outcomes.

PURPOSE: Although EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) induce favorable responses as first-line non-small cell lung cancer treatments, drug resistance remains a serious problem. Meanwhile, thermal therapy also shows promise as a cancer therapy strategy. Here we combine a novel EGFR-TKI treatment with thermal therapy to improve lung cancer treatment outcomes. RESULTS: The results suggest that the cAMP-H3BO3 complex effectively inhibits EGFR auto-phosphorylation, while inducing apoptosis and cell cycle arrest in vitro. Compared to the negative control, tumor growth was significantly suppressed in mice treated with oxidative phosphorylation uncoupler thyroxine sodium and either cAMP-H3BO3 complex or cAMP-H3BO3 complex (P < 0.05). Moreover, the body temperature increase induced by treatment with thyroxine sodium inhibited tumor growth. Immunohistochemical analyses showed that A549 cell apoptosis was significantly higher in the cAMP-H3BO3 complex plus thyroxine sodium treatment group than in the other groups. Moreover,Ca2+ content analysis showed that the Ca2+ content of tumor tissue was significantly higher in the cAMP-H3BO3 complex plus thyroxine sodium treatment group than in other groups. MATERIALS AND METHODS: Inhibition of EGFR auto-phosphorylation by cAMP and cAMP-H3BO3 complex was studied using autoradiography and western blot. The antitumor activity of the novel EGFR inhibitor (cAMP-H3BO3 complex) with or without an oxidative phosphorylation uncoupler (thyroxine sodium) was investigated in vitro and in a nude mouse xenograft lung cancer model incorporating human A549 cells. CONCLUSIONS: cAMP-H3BO3 complex is a novel EGFR-TKI. Combination therapy using cAMP-H3BO3 with thyroxine sodium-induced thermal therapy may improve lung cancer treatment outcomes.

EGFR induces DNA decomposition via phosphodiester bond cleavage.

EGFR may induce DNA degradation. This activity had not been previously described as an EGRF function. To confirm this unexpected activity, testing of EGFR in the presence of ATP and either 5A, 5C, 5G, 5T, or 5U oligonucleotides was performed. HPLC-MS analysis demonstrated that 5A and 5U levels significantly decreased in the presence of EGFR. Furthermore, fragments 4A and 4U were produced in 5A+EGFR+ATP and in 5U+EGFR+ATP reaction mixtures, respectively, but not in EGFR-negative controls. Degradation of Poly(A), Poly(C), Poly(G), Poly(I), Poly(T), and Poly(U) oligomers in the presence of EGFR and ATP correlated with the lower ability of reaction products to pair with complementary oligonucleotides. Gel electrophoresis showed that breakdown products migrated more quickly than controls, especially after addition of paired (complementary) oligomers, Poly(A) and Poly(U). Furthermore, λ DNA reaction products also migrated more quickly after incubation with EGFR. The results suggest that EGFR can induce breakage of certain types of nucleotide phosphodiester bonds, especially within the A residues of DNA or U residues of RNA, to induce DNA or RNA decomposition, respectively. This activity may be important in EGRF signaling, DNA degradation, or repair in normal or cancer cell activities.

Distribution of As, Cd, and Pb in seafood in Southern China and their oral bioavailability in mice.

The distribution of the toxic elements As, Cd, and Pb in nine different types of seafood from Shenzhen, China, was investigated by using inductively coupled plasma mass spectrometry (ICP-MS). The results revealed that the concentrations of arsenic (As) in fish (Lutjanus erythropterus, Paralichthys olivaceus) and in bivalve (Meretrix meretrix) and cadmium (Cd) in scallop (Argopecten irradians) exceed the limits established by food safety regulations in China and EU (European Union). Furthermore, the bioavailability of As, Cd, and lead (Pb) in mice after 20-day oral ingestion of Crassostrea rivularis was investigated, and the total rate of absorption of toxic elements in samples from the liver and kidney tissues and blood was determined. The results of this in vivo trial indicated that the oral bioavailability of As, Cd, and Pb was approximately 0.33, 0.45, and 0.74%, respectively.

The study of lead content distribution in Chinese seafood and its oral bioavailability in mice.

Using inductively coupled plasma mass spectrometry (ICP-MS), the lead concentrations and isotope ratios of 32 kinds of seafood collected from local markets of China were measured. Among these seafoods, the highest concentrations of lead were found in Patinopecten yessoensis and Mugil cephalus, which were 2.94 ± 0.40 and 2.02 ± 0.26 µg g(-1) of dry weight, respectively. Pb concentration was found to be higher in benthic fish than in other fish. The result indicated that lead concentrations in some seafood exceeded the maximum levels of Pb in foods proposed by European Commission (EC). Nine species of cooked seafood were chosen to feed mice (35-38 g). The result showed that Pb oral bioavailability of cooked seafood in vivo was below 10%. Furthermore, oral bioavailability of the same lead-containing seafood increased greatly in pregnant mice compared with non-pregnant mice.

Environmental lead pollution threatens the children living in the Pearl River Delta region, China.

INTRODUCTION AND PURPOSE: The objective of this study is to determine children's blood lead levels and identify sources of lead exposure. Childhood lead exposure constitutes a major pediatric health problem today in China. A blood lead screening survey program for children in the age group of 2-12 years residing in Pearl River Delta region, south of China, was carried out from Dec 2007 to Jan 2008. METHODS: Blood lead levels and lead isotope ratios of a total of 761 participants were assessed by inductively coupled plasma mass spectroscopy. Measurements of urban environmental samples for source identification of children lead exposure were also performed. RESULTS AND CONCLUSIONS: The geometric mean value of the children's blood lead levels was 57.05 µg/L, and 9.6% of them were higher than 100 µg/L. The blood lead levels were still much higher than those in developed countries. Based on the data of environmental lead source inventories, lead isotopic tracing revealed that there is about 6.7% past used gasoline Pb embedded in Shenzhen residential dust and about 15.6% in Guangzhou dust, respectively.

Study of lead level during pregnancy by application of synchrotron radiation micro XRF.

In order to study the daily Pb absorption in fetus and to monitor the main Pb sources in prenatal fetus, we have investigated several cases of Pb distribution along the longitudinal axis of fetal hair. The changes of Pb levels in the pregnancy period, even the daily changes of Pb levels can be detected in the hair. Therefore, by analyzing the Pb distribution curves in the fetal hair and the living habits of their mothers, the main sources of Pb in the prenatal fetus can be evaluated. In our study, the main sources of Pb in the two cases of prenatal fetus studied here should be from the polluted aquatics.

A source study of atmospheric polycyclic aromatic hydrocarbons in Shenzhen, South China.

Air pollution has become a serious problem in the Pearl River Delta, South China, particularly in winter due to the local micrometeorology. In this study, atmospheric polycyclic aromatic hydrocarbons (PAHs) were monitored weekly in Shenzhen during the winter of 2006. Results indicated that the detected PAHs were mainly of vapor phase compounds with phenanthrene dominant. The average vapor phase and particle phase PAHs concentration in Shenzhen was 101.3 and 26.7 ng m( - 3), respectively. Meteorological conditions showed great effect on PAH concentrations. The higher PAHs concentrations observed during haze episode might result from the accumulation of pollutants under decreased boundary layer, slower wind speed, and long-term dryness conditions. The sources of PAHs in the air were estimated by principal component analysis in combination with diagnostic ratios. Vehicle exhaust was the major PAHs source in Shenzhen, accounting for 50.0% of the total PAHs emissions, whereas coal combustion and solid waste incineration contributed to 29.4% and 20.6% of the total PAHs concentration, respectively. The results clearly indicated that the increasing solid waste incinerators have become a new important PAHs source in this region.

Synchrotron microradiography study on acute lung injury of mouse caused by PM(2.5) aerosols.

In order to investigate FeSO(4), ZnSO(4) (the two of main metal compositions of Shanghai PM(2.5) (particle matter with those aerodynamical diameter <2.5 microm)) effects on acute lung injury, six solutions contained PM(2.5) aerosol particles, FeSO(4), ZnSO(4) and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO(4) contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO(4) contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM(2.5)+FeSO(4)+ZnSO(4) was more serious than other toxin solutions. Results suggested that FeSO(4) mainly induced hemorrhage and ZnSO(4) mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM(2.5).

Study of the toxicological mechanism of acidified aerosols.

More than 30 aerosol samples were collected from 1 place near Zaojiaban Road (downtown of Shanghai) and 1 village near Jiading country (suburb) by a stacked-filter air sampler. The coarse particulates (>2.5 microm) and the fine particulates (PM2.5) and their unsoluble parts were analyzed by proton-induced X-ray emission. The cytotoxicity of particulates from the two places was evaluated by malondialdehyde (MDA) and thiazolyl blue (MTT) methods. The results show that the transition metal Fe, Cr, and Mn compounds from downtown are more easily soluble than those from the suburb, both in coarse and fine particulates, and the S content is much higher in particulates from downtown than that from the suburb. The cytotoxicity of the particulates from downtown is higher than that from the suburb and the cytotoxicity of acidified particulates is significantly higher than that of the controls. Because there are higher-soluble transition metal compounds that can induce free radicals in acidified particulates, the soluble transition metals may be one of the main factors for cytotoxicity.