Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode.

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ctDNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12, the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 (D-12) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV-vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 (D-12) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.

Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors.

The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.

Research on Treatment of Oily Sludge from the Tank Bottom by Ball Milling Combined with Ozone-Catalyzed Oxidation.

Difficult separation of oil-solid phase and high fine content of the recovered oil were two problems in the treatment of oily sludge from the tank bottom by the hot water-based extraction process. To solve the problems, one technology with "ball milling + ozone-catalyzed oxidation" as the core was studied, and the process parameters of ball milling and ozone-catalyzed oxidation were respectively optimized. After ball milling treatment, the oil content of dry oily sludge decreased from 33.9 to 10.2%. Then, an ozone catalytic oxidation treatment technology with aluminum ore as the catalyst was developed to further treat this stubborn oily sludge. Under the optimal conditions, the oil content of oily sludge could be further reduced to 0.28%, which met the treatment and disposal requirements stipulated in GB4284-2018. For further research on the contribution of the catalyst to the ozone catalytic oxidation system, the reaction activation energy and reaction rates of ozone oxidation and ozone catalytic oxidation were compared from the perspective of kinetics. The results showed that, with the catalyst addition, the reaction rate constants increased about three times and the reaction activation energy reduced 82.26%, which showed the effectiveness of the catalyst on the kinetics quantitatively. The combined process with "ball milling + ozone-catalyzed oxidation" as the core can solve the two problems in the treatment of oily sludge from the tank bottom by hot water-based extraction and provides a reference for the harmless and resourceful treatment of oily sludge from the tank bottom.

The control of clonorchiasis in Guangdong province, southern China.

Oriental liver fluke disease (clonorchiasis), caused by Clonorchis sinensis, is endemic in 81 counties in Guangdong province, China. This study was conducted following increasing lack of clonorchiasis awareness and increased consumption of raw freshwater fish and raw fish porridge at home and restaurants, which has been attributed to improved living standards in China, and is considered to have led to a higher C. sinensis infection rate in the country. A total of 61,517 individuals were investigated from 123 sites during a provincial survey in 1988, with average C. sinensis infection rate of 1.82% that increased to 4.08% (335/8217) in 1997. Higher infection rate was observed in adult men than women, with heavy infection rate in fishermen and businessmen because they have access and means to get raw fishes for consumption. Thus, clonorchiasis has become a serious public health problem in Guangdong province. Efforts targeting clonorchiasis prevention and control in Guangdong province started in the 1990s. These included carrying out large-scale surveys and chemotherapy in epidemic regions, research on promotion of environmental sanitation and methods for freshwater aquaculture. Establishment and promotion of clonorchiosis demonstration plots for comprehensive control measures, as well as the development of clonorchiasis-prevention community-out-patient clinics were initiated and their effectiveness was evaluated. However, there seem to be no obvious decline in the prevalence of C. sinensis with 4.90% (608/12,401) in 2015, at Guangdong province due to the people's habit of eating raw fishes in endemic areas. This has led to increasing calls to improve environmental sanitation in the aquaculture industry. It is, however, believed that control efforts on clonorchiosis in the province are at an early stage and require strengthening through the cooperation of different departments to work out effective strategies for sustainable field application of control mechanisms.

Small-scale spatial analysis of intermediate and definitive hosts of Angiostrongylus cantonensis.

BACKGROUND: Angiostrongyliasis is a food-borne parasitic zoonosis. Human infection is caused by infection with the third-stage larvae of Angiostrongylus cantonensis. The life cycle of A. cantonensis involves rodents as definitive hosts and molluscs as intermediate hosts. This study aims to investigate on the infection status and characteristics of spatial distribution of these hosts, which are key components in the strategy for the prevention and control of angiostrongyliasis. METHODS: Three villages from Nanao Island, Guangdong Province, China, were chosen as study area by stratified random sampling. The density and natural infection of Pomacea canaliculata and various rat species were surveyed every three months from December 2015 to September 2016, with spatial correlations of the positive P. canaliculata and the infection rates analysed by ArcGIS, scan statistics, ordinary least squares (OLS) and geographically weighted regression (GWR) models. RESULTS: A total of 2192 P. canaliculata specimens were collected from the field, of which 1190 were randomly chosen to be examined for third-stage larvae of A. cantonensis. Seventy-two Angiostrongylus-infected snails were found, which represents a larval infection rate of 6.1% (72/1190). In total, 110 rats including 85 Rattus norvegicus, 10 R. flavipectus, one R. losea and 14 Suncus murinus were captured, and 32 individuals were positive (for adult worms), representing an infection rate of 29.1% of the definitive hosts (32/110). Worms were only found in R. norvegicus and R. flavipectus, representing a prevalence of 36.5% (31/85) and 10% (1/10), respectively in these species, but none in R. losea and S. murinus, despite testing as many as 32 of the latter species. Statistically, spatial correlation and spatial clusters in the spatial distribution of positive P. canaliculata and positive rats existed. Most of the spatial variability of the host infection rates came from spatial autocorrelation. Nine spatial clusters with respect to positive P. canaliculata were identified, but only two correlated to infection rates. The results show that corrected Akaike information criterion, R2, R2 adjusted and σ2 in the GWR model were superior to those in the OLS model. CONCLUSIONS: P. canaliculata and rats were widely distributed in Nanao Island and positive infection has also been found in the hosts, demonstrating that there was a risk of angiostrongyliasis in this region of China. The distribution of positive P. canaliculata and rats exhibited spatial correlation, and the GWR model had advantage over the OLS model in the spatial analysis of hosts of A. cantonensis.

[The impurity profiling of paclitaxel and its injection by UPLC-MS/MS].

An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method was developed to elucidate the impurity profiles of paclitaxel and paclitaxel injections from different Chinese pharmaceutical companies. The fragmentation patterns for paclitaxel and the related impurities were analyzed and summarized. To remove the interference from auxiliary materials, such as hydrogenated castor oil, paclitaxel was dissolved in ethanol for acid, base, peroxide, and light induced forced degradation analysis, which could produce all the impurities exist in the paclitaxel injection. A total of 10 impurities were characterized, such as cephalomannine (1), 7-epi-10-deacetylpaclitaxel (2), 7-epipaclitaxel (3), baccatin Ⅲ (4), ethyl ester side chain (5), 7-epi-baccatin Ⅲ (6), 10-deacetylpaclitaxel (7), paclitaxel isomer(C3-C11 bridge) (8), paclitaxel isomer (9), and N-benzoyl-(2R,3S)-3-phenylisoserine (10), respectively. Among them, compounds 1-3 could be introduced during manufacture processing. In the forced degradation studies, while acid induced degradation products included 3-7, base induced degradation could produce 2-7 and 10; while 7 is the main compound produced by hydrogen peroxide treatment, 4 compounds (3-5 and 7) were produced by high temperature environment and 5 compounds (2-5 and 9 which is the first reported) from intensity light exposure. Furthermore, 8 was the main impurity came from intensity light exposed paclitaxel powder. The results from this study provide an important reference in processing, optimization, quality control and evaluation of paclitaxel.

Risk factors for Enterobius vermicularis infection in children in Gaozhou, Guangdong, China.

BACKGROUND: Enterobius vermicularis infection is a prevalent intestinal parasitic disease in children. In this study, we explored the epidemiological status and risk factors for E. vermicularis infection in children in southern China. METHODS: A cross-sectional survey was carried out in Gaozhou city, Guangdong province, China, in December 2011. Children aged 2-12 years from five schools participated in the study. The adhesive cellophane-tape perianal swab method was applied to detect E. vermicularis infection, while a questionnaire was sent to each child's guardian(s) to collect demographic and socioeconomic data, as well as hygiene behaviors, pertaining to each child. Univariate and multivariate logistic regression analyses were performed to capture the potential risk factors. RESULTS: Out of the 802 children surveyed, 440 were infected with E. vermicularis, with an average prevalence of 54.86 %, and a range from 45.96 to 68.13 %. The age variable was found to be statistically significant, whereas the sex variable was not. It was found that a mother's education level (low) and not washing hands before dinner were major risk factors in all children (802). After stratification by age, a father's education level (primary or below) and biting pencils (or toys) were significant risk factors in the younger children (508), while not washing hands before dinner and playing on the ground were important risk factors in the older children (294). CONCLUSION: This study demonstrates the prevalence of E. vermicularis infection in children in Gaozhou and reveals underlying risk factors. Most importantly, it reveals that risk factors differ among the different age groups, which indicates that different control measures targeted at particular age groups should be implemented.

[Distribution and schistosomiasis transmission risks of Biomphalaria straminea in inland China].

Biomphalaria straminea, the intermediary host of Schistosoma mansoni, was found by survey in local areas of Shenzhen City in 1981, which was the first finding of the snail in inland China. By 2013, the snail had spread in large range of Shenzhen City and overspread to the surrounding regions, Dongguan City and Huizhou City. Due to the facts that Shenzhen City has many international communications and is a key area of labor export, with high population mobility, while the reports of S. mansoni infection in the returnees of our country from Africa have been increasing recently, it must be paid a high attention to whether the epidemic or transmission of schistosomiasis mansoni may happen under the present circumstance. This paper initially discusses the finding, distribution, spreading and overspreading and transmission risk of B. straminea in inland China and puts forward some related control suggestions.

[Epidemiological analysis of malaria epidemic situation in Guangdong Province, 2011].

OBJECTIVE: To analyze the features of malaria epidemic in Guangdong Province in 2011 so as to provide the evidence for the elimination of malaria in Guangdong Province. METHODS: The data from the Disease Reporting Information System of Chinese Center for Disease Control and Prevention were analyzed with the descriptive epidemiological method for the epidemiological characteristics of malaria in Guangdong Province in 2011. RESULTS: A total of 96 malaria cases were reported in Guangdong Province in 2011, with an annual mean incidence of 0.092 per 100 thousand. There were 40 cases of Plasmodium vivax infection, 36 cases of Plasmodium falciparum infection and 20 cases of undivided malaria. There were 2 death cases. There were cases reported in 34 counties/cities/districts of 17 prefecture-level cities in the whole province. The cases distributed mainly in Guangzhou and Shenzhen, where there were 57 cases, reaching 59.38% of the cases of the whole province. There were cases reported every month in the whole year. From May to November, 73 cases were reported, accounting for 76.04% of the cases of the whole year. The ratio of male to female cases was 5.86: 1. The age distribution concentrated mainly on 20-50 years old. The youngest patient was 1 years old and the eldest was 65 years old. The occupation distribution concentrated mainly on the worker, commercial service, peasant, housekeeper and unemployed people (68 cases, 70.83%). In addition to the aforementioned 96 cases of local census register population, there were 32 cases of nonlocal census register population found in Guangdong, 2011. Of the total 128 cases, the main original areas of the imported cases were Africa (77, 60.16%) and Asia (30, 23.44%). The country with the most cases was Nigeria in Africa (36 cases), the second was Angola in Africa (19 cases), and the third was Myanmar in Asia (11 cases). CONCLUSION: The malaria epidemic situation in Guangdong Province is relatively stable in 2011, but the imported cases of Plasmodium falciparum infection increase. Therefore, the surveillance, prevention and control for imported cases of P. falciparum infection should be strengthened.

[Methods for grain size analysis of nanomedicines].

As nanomedicines are developing fast in both academic and market areas, building up suitable methods for nanomedicine analysis with proper techniques is an important subject, requiring further research. The techniques, which could be employed for grain size analysis of nanomedicines, were reviewed. Several key techniques were discussed with their principles, scope of applications, advantages and defects. Their applications to nanomedine analysis were discussed according to the properties of different nanomedicines, with the purpose of providing some suggestions for the control and administration of nanomedicines.

[Analysis and evaluation of the impurity of felodipine and its tablets].

The paper reports the systematic study on felodipine and its impurities in tablets, to improve its quality standards for the control of the related substances. HPLC-DAD, UPLC-MS, IR and NMR methods were used for the isolation of felodipine and its impurities in tablets, their identification and the zebrafish animal model was used for the analysis of the toxic impurities. In felodipine material and its tablets, three impurities are isolated and identified. They are impurity 1 [dimethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate], impurity 2 [ethyl methyl 4-(2, 3-dichlorophenyl)-2, 6-dimethylpyridine-3, 5-dicarboxylate] and impurity 3 [diethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate], separately. The result of zebrafish animal model analysis showed that the teratogenic effects of four compounds were: impurity 3 > or = felodipine > impurity 1 > impurity 2, lethal effects were as follows: impurity 2 = impurity 3 > felodipine > or = impurity 1. This study confirmed the toxicity of three impurities in felodipine. According to the results, the paper suggested the amendments to the standard of the medicine and provided the support to the control of impurities in the manufacturing process.

High performance liquid chromatographic separation of thirteen drugs collected in Chinese Pharmacopoeia 2010(Ch.P2010) on cellulose ramification chiral stationary phase.

The enantiomers separation of thirteen drugs collected in Ch.P2010 was performed on chiral stationary phase of cellulose ramification (chiralpak OD and chiralpak OJ) by high performance liquid chromatographic (HPLC) methods, which included ibuprofen (C1), ketoprofen (C2), nitrendipine (C3), nimodipine (C4), felodipine (C5), omeprazole (C6), praziquantel (C7), propranolol hydrochloride (C8), atenolol (C9), sulpiride (C10), clenbuterol hydrochloride (C11), verapamil hydrochloride (C12), and chlorphenamine maleate (C13). The mobile phase consisted of isopropanol and n-hexane. The detection wavelength was set at 254 nm and the flow rate was 0.7 mL/min. The enantiomers separation of these thirteen racemates on chiralpak OD column and chiralpak OJ column was studied, while the effects of proportion of organic additives, alcohol displacer and temperature on the separation were studied. And the mechanism of some of racemates was discussed. The results indicated that thirteen chiral drugs could be separated on chiral stationary phase of cellulose ramification in normal phase chromatographic system. The chromatographic retention and resolution of enantiomers could be adjusted by factors including column temperature and the concentration of alcohol displacer and organic alkaline modifier in mobile phase. It was shown that the resolution was improved with reducing concentration of alcohol displacer. When concentration of organic alkaline modifier was 0.2% (v/v), the resolution and the peak shape were fairly good. Most racemates mentioned above had better resolution at column temperature of 25 °C. When racemates were separated, the temperature should be kept so as to obtain stable separation results.

Aluminium-phosphorus interactions in plants growing on acid soils: does phosphorus always alleviate aluminium toxicity?

Aluminium (Al) toxicity and phosphorus (P) deficiency are considered to be the main constraints for crop production in acid soils, which are widely distributed in tropical and subtropical regions. Conventionally, P addition is regarded as capable of alleviating Al toxicity in plants. However, this field is still rife with unsubstantiated theories, especially for different plant species growing on acid soils. In this review, the responses of plants to different methods of Al-P treatments are briefly summarized, and possible reasons are proposed by considering recent results from our laboratory. It is shown that: (1) long-term Al-P alternate treatment is advantageous for studying Al-P interactions in plants; (2) under the long-term Al-P alternate treatment, the roles of P in Al phytotoxicity might be associated with the Al resistance capability and P use efficiency of the plant, and a P/Al molar ratio exceeding 5 in roots may be the threshold of P alleviating Al toxicity based on the calculation of the tested plants; (3) in acid soils, P application may be effective only after Al stress is overcome for Al-sensitive species. Thus it is concluded that P application does not always alleviate Al toxicity under long-term Al-P alternate treatment.

First provincial survey of Angiostrongylus cantonensis in Guangdong Province, China.

The rat lungworm Angiostrongylus cantonensis is a zoonotic nematode with a wide distribution. We report the first provincial survey of the prevalence of A. cantonensis infection among wild rodents and snails in Guangdong Province, China. A total of 2929 Pomacea canaliculata and 1354 Achatina fulica were collected from fields in 22 survey sites with a larval infection rates ranging from 0-26.6% to 0-45.4%. In addition, 114 Cipangopaludina sp and 252 Bellamya sp were bought from markets; larvae were found only in Bellamya snails from two survey sites with an infection rate of 1.4% (1/70) and 3.3% (3/91), respectively. Four hundred and ninety-one rodents were captured in nine sites (Rattus norvegicus, R. flavipectus, Suncus murinus, Mus musculus, Bandicota indica, R. losea and R. rattus). Adult worms were found in R. norvegicus, R. flavipectus and Bandicota indica. Our survey revealed a wide distribution of A. cantonensis and its intermediate hosts P. canaliculata and A. fulica in Guangdong. The prevalence of A. cantonensis in wild snails and rats poses a substantial risk for angiostrongyliasis in humans.

Selecting an appropriate interestingness measure to evaluate the correlation between Chinese medicine syndrome elements and symptoms.

To select the best interestingness measure appropriate for evaluating the correlation between Chinese medicine (CM) syndrome elements and symptoms, 60 objective interestingness measures were selected from different subjects. Firstly, a hypothesis for a good measure was proposed. Based on the hypothesis, an experiment was designed to evaluate the measures. The experiment was based on the clinical record database of past dynasties including 51 186 clinical cases. The selected data set in this study had 44 600 records. Cold and heat were selected as the experimental CM syndrome elements. Three indicators calculated according to the distances between two CM syndrome elements were obtained in the experiment and combined into one indicator. The Z score, ϕ-coefficient, and Kappa were selected from 60 measures after the experiment. The Z score and ϕ-coefficient were selected according to subjective interestingness. Finally, the ϕ-coefficient was selected as the best measure for its low computational complexity. The method introduced in this paper may be used in other similar territories.

[Endemic situation of schistosomiasis in Guangdong Province from 2004 to 2009].

OBJECTIVE: To understand the endemic situation of schistosomiasis in Guangdong Province. METHODS: The surveillance of Oncomelania hupensis snails and infectious sources was carried out in the former endemic areas, and the surveillance data were statistically analyzed from 2004 to 2009 according to the national and provincial surveillance protocols. RESULTS: From 2004 to 2009, an area of 927.45 hm2 was surveyed and no living snails were found, and 287 out of 12 345 young people living in the endemic areas showed serum positive with the DIGFA, but none of schistosomiasis patients were found. A total of 28 766 mobile population were involved in the DIGFA examination, and 417 persons were positive, among them, 52 chronic patients were found, and 6 patients had eggs in their stools. Through the passive surveillance, 281 cases were reported from 2003 to 2009, and 4 acute cases were reported from 2004 (1 case) to 2005 (3 cases). A total of 9 064 head of cattle were surveyed and none of them was infected with Schistosoma japonicum by stool examination. CONCLUSIONS: The achievements of schistosomiasis control are solidified in Guangdong Province. However, the risk of schistosomiasis transmission still remains. The surveillance should be continued, especially of imported infectious sources and snails.

[Investigation on Angiostrongylus cantonensis infection in rodents in Guangdong Province].

OBJECTIVE: To investigate the natural infection of Angiostrongylus cantonensis in Guangdong Province, and to provide the scientific evidence for control measures. METHODS: The investigation was carried out in 56 villages of 28 towns of 28 counties/districts in East Guangdong, West Guangdong, the mountain area of North Guangdong and Peal River Delta of the Province from 2005 to 2010. The rodents were captured with live trap and the species identified. Angiostrongylus cantonensis adult worms were collected from the hearts and lungs of rodents, examined, counted and the sex of worms identified. RESULTS: The rodents were captured from 2005 to 2010, belonged to 2 orders, 2 families (subfamily), 4 genera and 10 species. Seven species of the rodents were found infected with Angiostrongylus cantonensis in all 28 counties/districts. Totally 5 820 rats were examined and 496 infected ones were identified, with a mean infection rate of 8.52%. The infection rate of rodents was highest in the Peal River Delta, reaching 9.8% (205/2084) (chi2=15.25, P<0.01). Rattus norvegicus had the highest infection rate of 16.9% (310/1 835) (chi2=240.91, P<0.01). The mean intensity of infection was 6.1 worms/rat. 1 125 female and 1064 male worms were found respectively (chi2=1.75, P>0.05). CONCLUSION: Natural infection of Angiostrongylus cantonensis in rodents has been found in all the 56 villages selected from the 4 regions of Guangdong Province.

The TCM pattern of the six-zang and six-fu organs can be simplified into the pattern of five-zang and one-fu organs.

OBJECTIVE: To simplify the TCM pattern of the zang-fu organs. METHODS: A database of zang-fu syndromes was established. The relationship between the zang-fu syndromes was analyzed by means of frequency analysis, association rule, and phi-coefficient correlation. RESULTS: The six zang-fu organs of the heart, liver, spleen, lung, kidney, and stomach prove to be the main components of the zang-fu pattern. The large intestine, small intestine, gallbladder, bladder, triple energizer, and pericardium have strong association and positive correlation with the above-mentioned six zang-fu organs, and their clinical symptoms can all be included into the symptoms of these six zang-fu organs. CONCLUSION: The traditional TCM pattern of six-zang and six-fu can be simplified into five-zang and one-fu.

[Raman spectroscopy fluorescence background correction and its application in clustering analysis of medicines].

During Raman spectroscopy analysis, the organic molecules and contaminations will obscure or swamp Raman signals. The present study starts from Raman spectra of prednisone acetate tablets and glibenclamide tables, which are acquired from the BWTek i-Raman spectrometer. The background is corrected by R package baselineWavelet. Then principle component analysis and random forests are used to perform clustering analysis. Through analyzing the Raman spectra of two medicines, the accurate and validity of this background-correction algorithm is checked and the influences of fluorescence background on Raman spectra clustering analysis is discussed. Thus, it is concluded that it is important to correct fluorescence background for further analysis, and an effective background correction solution is provided for clustering or other analysis.