Synthesis of estrone selenocyanate Compounds, anti-tumor activity evaluation and Structure-activity relationship analysis.

Introducing different functional groups into steroid can bring unexpected changes in biological activity of the steroid. Using estrone as a raw material, through the functional group conversion and modification of the 17-carbonyl, the structural fragments with selenocyano groups were instilled in the form of amide, ester, and oxime ester, respectively, and various 17-substituted estrone selenocyanate derivatives were synthesized. In addition, different 3-substituted estrone selenocyanate derivatives were synthesized by introducing different selenocyanoalkoxy fragments into the 3-position of estrone in the form of alkyl ether. Furthermore, the selenocyano-containing moieties were embedded into the 2-position of estrone by means of amide, affording diverse 2-selenocyanoamide-estrone derivatives. The antiproliferative activities of the target compounds were screened by selecting tumor cell lines related to the expression of human hormones. The results showed that the introduction of selenocyano group into estrone could endow estrone with significant biological activity of inhibiting the proliferation of tumor cells. Structure-activity relationship research showed that the cytotoxicity of 3-selenocyanoalkoxy-estrone was further increased with the extension of alkyl carbon-chain within 8 carbon chain lengths. In addition, the cytotoxicity of the products with selenocyano via the form of amide was stronger than that of ester or ether. Selenocyano moiety instilled at the 2-position of estrone in the form of amide was more cytotoxic than that of 17- or 3-position. Among them, compound 21a has better inhibitory activity on tested tumor cells than positive controls Abiraterone and 2-methoxyestradiol. Research showed that the compound 21c induced programmed apoptosis in Sk-Ov-3 cancer cells, and compound 17d inhibited significantly the growth of human cervical cancer zebrafish xenografts in vivo, offering useful insights into the synthesis of steroid antitumor drugs.

Study on the preparation of sustained-release thiamethoxam microspheres by blending microcrystalline wax with tapioca starch ester or dehydroabietic acid ester as the matrix.

The controlled release formulations (CRFs) are considered an effective way to solve damage to the environment caused by traditional pesticide formulations. To change the defects of traditional neonicotinoid formulations that dissolve quickly in soil, three types of thiamethoxam (TM) CRFs microspheres with content of 20% TM were prepared using microcrystalline wax (MK) as the matrix, laurate acid tapioca starch ester (MSK) and stearyl dehydroabietic acid ester (MDK) as the regulators of ingredient release. The release behavior of CRFs microspheres in water and soil showed that the microspheres had superior stability and different TM sustained-release periods, and TM release of the microspheres in soil was faster than that in water. The release rate is TM/MDK > TM/MSK > TM/MK. In water, the release of thiamethoxam technical was finished after 38 hours. However, for TM/MK, the release rate was 94% after 240 hours, and the release time was extended by 6 times. Meanwhile, TM/MDK has a particular pH-responsive release. Research shows that using microcrystalline wax as the matrix, by adding MSK or MDK to adjust the release of ingredients, pesticide CRFs microspheres with different release periods can be prepared to achieve the purpose of controlling the release of pesticides.

3D DNA Scaffold-Assisted Dual Intramolecular Amplifications for Multiplexed and Sensitive MicroRNA Imaging in Living Cells.

The simultaneous live-cell imaging of multiple intracellular and disease-related microRNAs (miRNAs) with low abundances is highly important to enhance specificity and accuracy for disease diagnosis. On the basis of the improved cell internalization and accelerated reaction kinetics, we develop a three-dimensional (3D) DNA nanoprobe that integrates intramolecular DNAzyme (intra-Dz) and catalytic hairpin assembly (intra-CHA) amplifications to simultaneously monitor multiple miRNAs in living cells. The sensing components are loaded on a DNA scaffold via the sticky-end hybridization of the DNA sequences to increase the local concentrations of the signal probes. The miRNA-21 and miRNA-155 target sequences can trigger intra-Dz and -CHA amplifications on the nanoprobes to show significantly amplified and distinct fluorescence at different wavelengths for simultaneously monitoring low levels of miRNAs. Real-time fluorescence microscopy reveals that such a 3D DNA nanoprobe design with the intra-Dz and -CHA amplifications can accelerate the reaction rate compared to that of the conventional free Dz and CHA because of the increased local concentrations of the sensing components. Importantly, the 3D DNA nanoprobe has desirable stability and biocompatibility and can be readily delivered into living cells to achieve multiplexed and highly sensitive sensing of intracellular miRNA-155 and miRNA-21 sequences. With the demonstration of its intracellular application, the developed 3D DNA nanoprobe thus holds promising potential for biological studies and accurate disease diagnosis.

Fabrication and evaluation of Lambda-Cyhalothrin nanosuspoemulsion with pH- and temperature-responsive based on polyethylene wax as carrier.

Using polyethylene wax (PW) as the coating matrix, the lambda-cyhalothrin-PW nanosuspoemulsion (LC-PW) with a particle size of 80-150nm was prepared through high-speed stirring, hot melt emulsification and ultrasonic dispersion. The formulation and composition of the LC-PW were optimized, the morphology of the LC-PW was analyzed by dynamic light scattering (DLS) and TEM, and the structure of the LC-PW was characterized by UV and IR. The anti-photolysis test showed that LC-PW had a good anti-photolysis performance. Furthermore, LC-PW could sustainably release Lambda-cyhalothrin, which was pH- and temperature dependent. The insecticidal activity analysis in the greenhouse indicated that the toxic strength between LC-PW and LC-SC (lambda-cyhalothrin-suspension concentrate) to Mythimna separata was similar within the same concentration ranges tested, but the insecticidal duration of LC-PW was significantly longer than LC-SC. Thus, the new type of LC-PW with the properties of anti-photolysis and controlled release is suitable for application in the field as a better insecticide.

Maternal inorganic mercury exposure and renal effects in the Wanshan mercury mining area, southwest China.

This study evaluated the relationship between urine mercury (UHg) concentrations and renal function (serum creatinine (SCr) and blood urea nitrogen (BUN)) in delivery women in the Wanshan mercury (Hg) mining area. Leishan County was selected as the control area. 165 and 65 maternal samples were collected from the Wanshan and Leishan area, respectively. The geometric means of UHg concentrations were 1.09 and 0.29 µg/L in Wanshan and Leishan subjects, respectively. Significant differences (p < 0.01) of UHg were observed between the two populations, indicating the potential risks of inorganic Hg exposure in the Wanshan population. The median (interquartile range) values of SCr were 69.1 (12.5) µmol/L and 46.0 (11.0) µmol/L for the Wanshan and Leishan populations, respectively, indicating significant differences (p < 0.01) between the two groups. However, no significant differences among BUN values for the two groups were observed. A significant positive correlation (r = 0.385, p < 0.001) was observed between UHg concentration and SCr in the study population. The odds ratio (OR) value of UHg in Wanshan area was 9.29 times higher than that in Leishan area (95% confidence interval (CI): 3.58-24.1). The OR value of SCr decrease in patients with low UHg was 0.32 times higher than that in patients with high UHg (95% CI: 0.19-0.55). The OR value of SCr decrease in the population with fish consumption was 0.71 times higher than that of the population without fish consumption (95% CI: 0.58-0.88). In conclusion, maternal IHg exposure caused impaired renal function and fish consumption may play a role in preventing Hg-induced nephrotoxicity.

Release-controlled microcapsules of thiamethoxam encapsulated in beeswax and their application in field.

Using beeswax as wrapping matrix, two types of release-controlled TM (thiamethoxam)/BK(beeswax-kaolin) microcapsules were prepared by adsorbing TM on kaolin and then encapsulated with beeswax, or directly wrapping TM with beeswax. The structure and morphology of the TM/BK microcapsules were characterized. The effects of different preparation methods, the particle size, pH conditions and different additives on the release property of the TM/BK microcapsules were investigated in water and soil column to compare the advantages of the two approaches. Finally, the insecticidal effect of the TM/BK microcapsules against sugarcane borer and rice planthopper was tested. The results show that the TM/BK microcapsules have a better sustained-release in both water and soil, and the release rate is different under different pH conditions. In addition, the releasing time of the TM/BK microcapsules can be modified by different preparation methods and combination of different additives. In the field applications, the insecticidal activity of the TM/BK microcapsules was better than that of non-sustained control group. Especially in the rice field test, 45 days after the application, the control group lost the activity against rice planthopper because of drug loss, whereas the TM/BK microcapsule group still retained about 90% of the insecticidal activity. The results suggest that the microcapsules have better agricultural application for insect control.

Chronic Methylmercury Exposure Induces Production of Prostaglandins: Evidence From A Population Study and A Rat Dosing Experiment.

Methylmercury (MeHg) is a well-known environmental neurotoxicant affecting millions worldwide who consume contaminated fishes and other food commodities. Exposure to MeHg has been shown to associate positively with some chronic diseases including cardiovascular diseases, but the mechanism is poorly characterized. MeHg had been shown to affect prostaglandin (PG) regulations in in vitro studies, but neither in vivo nor human studies investigating the effects of MeHg on PG regulations has been reported. Thus, the current study aimed to investigate the association between MeHg exposure and serum PG concentrations in a cross-sectional study among human adults followed by a validation investigation on the cause-effect relationship using a rat model. First, a total of 121 women were recruited from two cities: Wanshan and Leishan in Guizhou, China. Statistical analysis of the human data showed a positive association between blood total mercury (THg) levels and serum concentrations of PGF2α, 15-deoxy-PGJ2, and PGE2 after adjusting for site effects. In the animal study, adult female Sprague-Dawley rats were dosed with 40 µg MeHg/kg body weight/day for 12 weeks. Serum 15-deoxy-PGJ2 and 2,3 d-6-keto-PGF1α concentrations were found to increase significantly after 6 and 10 weeks of MeHg dosing, respectively, while serum PGF2α concentration increased significantly after 12 weeks of MeHg dosing. Combined results of our human and rat studies have shown that chronic MeHg exposure induced dysregulation of PG metabolism. As PGs are a set of mediators with very diverse functions, its abnormal production may serve as the missing mechanistic link between chronic MeHg exposure and various kinds of associated clinical conditions including neurodegeneration and cardiovascular diseases.

Synthesis of Vorinostat and cholesterol conjugate to enhance the cancer cell uptake selectivity.

Histone deacetylase (HDAC) inhibitors modulate various cellular functions including proliferation, differentiation, and apoptosis. Vorinostat (SuberAniloHydroxamic Acid, SAHA) is the first HDAC inhibitor approved by FDA for cancer treatment. However, SAHA distributes in cancer tissue and normal tissue in similar levels. It will be ideal to selectively deliver SAHA into cancer cells. Rapidly growing cancer cells have a great need of cholesterol. Low-density lipoprotein (LDL) is the major cholesterol carrier in plasma and its uptake is mediated by LDL-receptor (LDL-R), a glycoprotein overexpressed on the surface of cancer cells. Herein, we designed and synthesized a SAHA cholesterol conjugate, and further formed the conjugate containing particles with LDL as the carrier. The diameters of the particles were determined. The inhibitory activity of the particles carrying the conjugate was determined with cancer cell proliferation assay, and the hydrolysis of the conjugate by the enzymes in cancer cells was confirmed with LC-MS/MS.

Copalic acid analogs down-regulate androgen receptor and inhibit small chaperone protein.

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well.

Indomethacin derivatives as tubulin stabilizers to inhibit cancer cell proliferation.

Cyclooxygenase (COX) inhibitor Indomethacin analogs exhibited more potent cancer cell growth inhibition and apoptosis inducing activities than the parental compound. The anti-proliferative mechanism investigation of the analogs revealed that they inhibited tubulin polymerization at high concentrations whereas enhanced polymerization at low concentrations. The two opposite activities might antagonize each other and impaired the anti-proliferative activity of the derivatives eventually. In this study, we further performed lead optimization based on the structure activity relationship (SAR) generated. One of the new Indomethacin derivatives compound 11 {2-(4-(benzyloxy)phenyl)-N-(1-(4-bromobenzoyl)-3-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-2-methyl-1H-indol-5-yl)acetamide} inhibited the proliferation of a panel of cancer cell lines with IC50s at the sub-micromole levels. Further study revealed that the compound only enhanced tubulin polymerization and was a tubulin stabilizer.

Synthesis and in vitro antiproliferative evaluation of some B-norcholesteryl Benzimidazole and Benzothiazole derivatives.

Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3ß'-Acetoxy-5ß'-hydroxy-6'-B-norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.

Synthesis and evaluation of some new aza-B-homocholestane derivatives as anticancer agents.

Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D) multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR) generated in the studies is valuable for the design of novel chemotherapeutic agents.

[Analysis mediating effect of self-efficacy between diet-related cognitive and behavioral].

OBJECTIVE: To investigate the influence of self-efficacy between diet-related cognitive and behavioral by introducing the concept of mediating effect in children and adolescents. METHODS: Using multistage cluster sampling, 9 middle and primary school at 1 downtown area and 2 county areas in Guizhou province were selected. Referencing to the foreign-related research and design of the questionnaire, 1398 students were included. The general survey and the correlation analysis about the cognition and self-efficacy of related diet, the favorable behavior related health and the unfavorable behavior related health were conducted. Using the regression analysis and building the modeling to test the mediating effect of self-efficacy of related diet. RESULTS: The average scores of the cognition, self-efficacy and beneficial health's behavior of related diet were not high. There were significant correlation between the cognition and self-efficacy, the cognition and favorable behavior, the self-efficacy and favorable behavior, the favorable behavior and unfavorable behavior. The correlation coefficients were 0.292, 0.248, 0.228 and -0.102 (P < 0.01). The self-efficacy had significant indirect mediating effect between diet-related cognitive and beneficial health's behavior, the indirect mediating effect was 24.52% of the total effect. Bringing into the structural equation model to test, the indirect effect of self-efficacy (namely mediating effect) was more obvious (beta = 0.39, P < 0.01). CONCLUSION: In the actual dietary behavior of children and adolescents, improving the self-efficacy can increase the degree of changing in behavior which acted by the cognition.

Enhancing Systemic Translocation of Insecticides via Nanoformulations Incorporating ß-Cyclodextrin Octadecarboxylate as a Carrier.

The conversion of contact-killing pesticides into systemic pesticides can significantly enhance the bioavailability of pesticides, thereby reducing pesticide usage and environmental harm. A series of ß-cyclodextrin fatty acid esters with varying branch chains were synthesized and employed as carriers in nanoformulation of insecticide. The investigation revealed that nanoformulations prepared using ß-cyclodextrin octadecarboxylate (ß-CDs) exhibited superior stability and remarkable systemic translocation within plants. Six contact-killing insecticide nanoformulations were developed utilizing ß-CDs as carriers, and tests indicated that ß-CDs significantly enhanced the systemic translocation of insecticides in plants compared to carrier-free nanoformulations. It was found that ß-CDs increased the level of systemic translocation of insecticides by 5-12 times. Additionally, characterization results from λ-cyhalothrin-ß-CDs nanoformulation demonstrated their superior ability to improve photolysis resistance, prolong release time, and extend insecticidal duration. Consequently, ß-CDs can be utilized as a green additive in pesticide production to enhance the systemic translocation of pesticides in plants and increase their bioavailability.

Synthesis and antiproliferative activity of C-homo-lactam derivatives of 7-deoxycholic acid.

Using deoxycholic acid as starting materials, a series of 12a-aza-C-homo-12-one 7-deoxycholic acid derivatives were synthesized The antiproliferative activity of the synthesized compounds against some carcinoma cell lines was investigated. The results showed that some 12-oxy-12a-aza-C-homo-7-deoxycholic acid derivatives displayed distinct cytotoxicity to HeLa (human cervical carcinoma) and Tu 686 (laryngocarcinoma) tumor cell lines. In particular, the IC50 values of the compounds 6 and 7 against Tu 686 cells are 16.7 and 19.8 µM/L respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.

Synthesis and evaluation of some 17-acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives as cytotoxic agents: structure/activity studies.

Using pregnenolone and 7-deoxycholic acid as starting materials, some 17-acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives were synthesized. The cytotoxicity of the synthesized compounds was tested in vitro against two tumor cell lines: SGC 7901 (human gastric carcinoma) and Bel 7404 (human liver carcinoma). The result showed that the blockage of the interaction of the amide group with outside groups might cause a decrease of the cytotoxicity, and an O-benzyloximino group at the 3-position of N,N-dimethyl-7-deoxycholic amide could enhance the cytotoxic activity of the compound. The information obtained from the studies provides the structure-activity relationship for these compounds and may be useful for the design of novel chemotherapeutic drugs.

Synthesis and Antiproliferative Activity Evaluation of B-norcholesterol-6- amide Compounds.

BACKGROUND: The structure modification of steroids is commonly used to change the biological activity of steroids in medicinal chemistry. In recent years, it has been found that some derivatives derived from the structural modification of cholesterol display good inhibitory activity against tumor cell proliferation in vitro. METHODS: Using cholesterol as the starting material, different types of B-norcholesterol-6-amide derivatives were synthesized by the reaction of 6-carboxyl-B-norcholesterol with different alkyl amines or 6-amino-B-norcholesterol with different acyl chlorides. The inhibitory activity of compounds on the proliferation of tumor cell lines was investigated by the MTT method. RESULTS: The results showed that the B-norcholesterol-6-amide compounds displayed distinct cytotoxicity against Sk-Ov-3 cells but caused no obvious damage against HEK-293T cells. Additionally, the steroidal amide derivatives formed from 6-amino-B-norcholesterol showed stronger cytotoxicity than those produced from 6-carboxyl-B-norcholesterol. Specially, compounds with chloroalkyl structure displayed significant inhibitory activity against all tumor cells tested. Among them, compounds 19-21 showed cytotoxicity like 2-methoxyestradiol as a positive control, and the IC₅₀ value of compound 20 on HeLa cells was 3.9 µM. CONCLUSION: After introducing chloroalkyl acyl groups into 6-position of 6-amino-B-norcholesterol, the cytotoxicity of resulting B-norcholesterol-6-amide compounds can be greatly enhanced.

Synthesis, characterization and application of emamectin-alkaline lignin conjugate with photolysis resistance and systemic translocation.

Controlled release formulations (CRFs) are a key technical approach for the sustainable development of pesticides. In this study, a CRF conjugate (emamectin-alkaline lignin, EB-AL) was successfully prepared using alkaline lignin as the substrate, with amide bond connecting emamectin and alkaline lignin. The structure and morphology of the conjugate were characterized using IR, 1HNMR, elemental analysis, SEM and TG. The release of EB-AL showed that the conjugate maintained its original structure when released in 50 % methanol-water and soil column, and the amide bond remained intact. The anti-photolysis test revealed that EB-AL had a 3.5 times higher photolysis half-life T0.5 than the general emamectin suspension concentrate (EB-SC). Bioactivity tests in the greenhouse demonstrated that EB-AL possessed a longer insecticidal duration and good biosafety. Ostrinia nubilalis lethality rate remained above 70 % for 19 days, while EB-EC, the control, had a rate of <50 % after 11 days of application. Additionally, EB-AL conjugate demonstrated excellent systemic translocation in plants, likely due to its ability to mediate alkaline lignin.

Straightforward synthesis of steroidal selenocyanates through oxidative umpolung selenocyanation of steroids and their antitumor activity.

Straightforward access to steroidal selenocyanates in a single assembly step from steroids remains a significant challenge. However, the development of novel method for the synthesis of steroidal selenocyanates and further investigation of their bioactivities have largely lagged behind. In this work, selenocyano groups were directly introduced into the 17- or 21-position of pregnenolone, the 2-position of estradiol, and the 16-position of estrone. A total of 16 estrogen selenocyanate derivatives with diverse structures were synthesized, and the tumor cell lines closely related to the expression level of estrogen were used to investigate the inhibitory activity of the target products on tumor cell proliferation in vitro. The results revealed that the 17-selenocyano-substituted pregnenolone selenocyanate derivatives 1b-3b exhibit obvious inhibitory activity against the tested tumor cell lines. Additionally, the 2-selenocyano-substituted estradiol derivatives and 16-selenocyano-substituted estrone derivatives exhibit selective inhibitory on HeLa cell lines. Among them, 2-selenocyano-3-methoxyestradiol-17-benzoate (7e) displayed an IC50 value of 4.1 µM against HeLa cells and induced programmed apoptosis in HeLa cancer cells. Furthermore, compound 7e could significantly inhibit the growth of human cervical cancer xenografts in zebrafish in vivo. This approach provides new insights for future steroid antitumor drug design.

Sustainable and cascaded catalytic hairpin assembly for amplified sensing of microRNA biomarkers in living cells.

The sensing of intracellular microRNAs (miRNAs) is of significance for early-stage disease diagnosis and therapeutic monitoring. DNA is an interesting building material that can be programed into assemblies with rigid and branched structures, especially suitable for imaging intracellular biomolecules or therapeutic drug delivery. Here, by introducing the palindromic sequences into the programmable DNA hairpins, we describe an endogenous target-responsive three-way branched and palindrome-assisted catalytic hairpin assembly (3W-pCHA) approach for imaging miRNA-155 of living tumor cells with high sensitivity. The miRNA-155 triggers autonomous assembly of the fluorescently quenched signal hairpin and two hairpin dimers formed via hybridization of their respective palindromic sequences to yield branched DNA junctions, which carry the unopened hairpins and thus provide addressable substrates for continuous assembly formation of DNA nanostructures. During the formation of the DNA nanostructures, the miRNA-155 is cyclically reused and many signal probes are unfolded to show highly intensified fluorescence for detecting miRNA-155 down to 6.9 pM in vitro with high selectivity. More importantly, these probes can be transfected into live cancer cells to initiate the assembly process triggered by intracellular miRNA-155, which provides a new way for imaging highly under-expressed miRNAs in cells. Besides, this approach can also be employed to differentiate miRNA-155 expression variations in different cells, indicating its promising potentials for early-stage disease diagnosis and biological studies in cells.