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Background:. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, are widely used to treat non-small cell lung cancer (NSCLC). However, acquired resistance is unavoidable, impairing the anti-tumor effects of EGFR-TKIs. It is reported that histone deacetylase (HDAC) inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy. However, whether the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can overcome erlotinib-acquired resistance is not fully clear. Methods:. An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures. NSCLC cells were co-cultured with SAHA, erlotinib, or their combination, and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting. Finally, the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was assessed by western blotting. Results:. The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line. PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells, and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells. Furthermore, treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone. Conclusions:. PTEN deletion is closely related to acquired resistance to EGFR-TKIs, and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy. SAHA enhances the suppressive effects of erlotinib in lung cancer cells, increasing cellular apoptosis and PTEN expression. SAHA can be a potential adjuvant to erlotinib treatment, and thus, can improve the efficacy of NSCLC therapy.

Background To evaluate whether the addition of taxanes to platinum and fluoropyrimidines in adjuvant chemotherapy would result in longer survival than platinum plus fluoropyrimidines in gastric cancer patients who received D2 gastrectomy. Methods Data of patients with gastric adenocarcinoma who received D2 gastrectomy and adjuvant chemotherapy with platinum plus fluoropyrimidines or taxanes, platinum plus fluoropyrimidines was retrospectively collected and analyzed. 1:1 Propensity score matching analysis was used to balance baseline characteristics between two groups. Survival curves were estimated using Kaplan-Meier method, and the differences were compared using the log-rank test. Results Four hundred twenty-five patients in the platinum plus fluoropyrimidines group and 177 patients in the taxanes, platinum plus fluoropyrimidines group were included into analysis. No statistical differences in disease-free survival and overall survival were observed between two groups. After propensity score matching, 172 couples of patients were matched, the baseline characteristics were balanced. The median disease-free survival were 15.8 months (95% CI, 9.3~22.4) in the platinum plus fluoropyrimidines group and 22.6 months (95% CI, 15.9~29.4) in the taxanes, platinum plus fluoropyrimidines group (HR = 0.63; 95% CI, 0.48~0.85; P = 0.002). The median overall survival was 25.4 months for patients in the platinum plus fluoropyrimidines group (95% CI, 19.4~31.3) and 33.8 months (95% CI, 23.5~44.2) for those in the taxanes, platinum plus fluoropyrimidines group (HR = 0.68; 95% CI, 0.53-0.87; log-rank test, P = 0.002). Conclusions For gastric adenocarcinoma patients, the adjuvant triplet combination of taxanes, platinum, and fluoropyrimidines regimen after D2 gastrectomy was superior to platinum plus fluoropyrimidines regimen in disease-free survival as well as overall survival. Trial registration This project has been registered in the Chinese Clinical Trial Registry (ChiCTR1800019978).

The development and immune recognition of natural killer (NK) cell are regulated critically by major histocompatibility complex (MHC) class I molecules. However, it remains unclear whether the function of NK cells is regulated by MHC class II molecules. To test this, we monitored the development, phenotype and function of NK cells by using MHC class II deficient (H2-/-) mice. The numbers and development of NK cells keep unaltered in H2-/- mice, compared with those in wide type (H2+/+) mice. A part of Ly49 family receptors on NK cells are down-regulated both in mRNA and protein expression in absence of MHC class II molecules. Furthermore, NK cells obtained from H2-/- mice exhibit more expression of CD69 and IFN-γ after cross-linking with NK1.1. Also, the cytotoxicity against tumor cell lines of NK cells from H2-/- mice was increased significantly. Taken together, our study indicates that the absence of MHC class II molecules promotes the activation and function of NK cells in mice.

BACKGROUND Alcoholic liver disease (ALD), an important cause of acute or chronic liver injury, results from binge drinking or long-term alcohol consumption. To date, there is no well-established mouse model with a comprehensive metabolic profile that mimics ALD in humans. This study aimed to explore the differential metabolic pathways and related differential metabolites in the liver of an ALD mouse model. MATERIAL AND METHODS A C57BL/6J mouse model of ALD was induced by alcohol feeding for 10 days plus binge alcohol feeding. The metabolomic profiles in the liver of the ALD mouse model was detected through ultra-high-pressure liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF-MS). RESULTS A total 35 metabolites were significantly altered during the development of ALD. These metabolites were correlated to multiple metabolic pathways, including purine metabolism, the pentose phosphate pathway, cysteine and methionine metabolism, D-glutamine and D-glutamate metabolism, pyrimidine metabolism, and vitamin B6 metabolism. CONCLUSIONS The findings of the present study reveal potential biomarkers of ALD, and provide further insights into the pathogenesis of ALD.

Peptide-spectrum matches (PSM) scoring between the experimental and theoretical spectrum is a key step in the identification of proteins using mass spectrometry (MS)-based proteomics analyses. Efficient protein identification using MS/MS data remains a challenge. The strategy of using RNA-seq data increases the number of proteins identified by re-constructing the custom search database and integrating mRNA abundance into the false discovery rate of post-PSM. However, this process lacks an algorithm that can allow the incorporation of mRNA abundance into the key scoring model of PSM. Therefore, we developed a novel PSM scoring model, which incorporates mRNA abundance for improved peptide and protein identification. In the new algorithm, abundance information of mRNA was transformed to the prior probability of protein identification and integrated to re-score in PSM using the binomial probability distribution model. Compared with other algorithms using five MS/MS datasets, the results showed that the least improvement ratios of peptide and protein groups were 3.39%-9.79% and 0.48%-8.16% in different datasets (human, rat, zebrafish, yeast, and Arabidopsis thaliana). The new strategy offers an effective solution for MS-based identification of peptides and proteins. SIGNIFICANCE: The new algorithm identifies proteins by quantifying mRNA abundance (FPKM) and incorporating it into a scoring model for peptide-spectrum matches. It is important to improve peptide and protein identification from MS/MS datasets in proteomics research.

To investigate the radiosensitizing effect and mechanism of action by the natural product Paeonol on lung adenocarcinoma both in vitro and in vivo.Two lung adenocarcinoma cell lines (human lung adenocarcinoma cell line A549 and mouse Lewis lung carcinoma (LLC) cell line) were chosen for this research. In order to select the experimental concentrations of Paeonol, cytotoxicity was determined using a MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide) assay. A clonogenic assay was performed to measure the radiosensitizing effects. Apoptosis was determined by the Tunel (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) assay and flow cytometry. Protein expression was analyzed by Western blotting. To test the radiosensitizing effect in vivo, a transplanted tumor model was established.The MTT assay showed that Paeonol inhibited proliferation of cells. Paeonol concentration ranged from an IC5 (5% inhibiting concentration) to an IC20 and was used at non-toxic concentrations for subsequent experiments. The clonogenic assay showed that Paeonol enhanced the radiosensitivity of cells. Data from the Tunel assay and flow cytometry verified that Paeonol enhanced radiation-induced apoptosis. Paeonol inhibited the activation of the PI3K/AKT (Phosphatidylinositol 3-kinase/ Protein Kinase B) pathway and down-regulated the expression of COX-2 (Cyclooxygenase-2) and Survivin. Paeonol (1718 mg/kg) combined with 10 Gy irradiation inhibited the growth of a transplanted tumor model in vivo, resulting in the longest tumor growth time, tumor growth delay and the highest inhibition ratio when compared with the radiotherapy alone group.It is reported for the first time that Paeonol has a radiosensitizing effect on lung adenocarcinoma both in vitro and in vivo. This effect could be related to the augmentation of radiation-induced apoptosis and the inhibition of the PI3K/Akt signalling pathway and its downstream proteins: COX-2 and Survivin.

Endoplasmic reticulum stress-mediated cell apoptosis is implicated in the development of cancer. Melatonin induces apoptosis in hepatocellular carcinoma (HCC) in experimental studies, but the effects of melatonin on endoplasmic reticulum (ER) stress-induced apoptosis in HCC have not been tested. Differences in ER stress-induced apoptosis in human hepatoma cells and normal human hepatocyte were investigated by exposure to tunicamycin (ER stress inducer). Significant differences were observed in the rate of apoptosis between HepG2 cells (hepatoma cells) and HL-7702 cells (normal human hepatocyte cells). The expression of cyclooxygenase-2 (COX-2) was increased in HepG2 cells but not in HL-7702 cells. Furthermore, down-regulation of COX-2 expression using the COX-2 inhibitor, celecoxib, increased tunicamycin-induced apoptosis concomitant with the up-regulation of pro-apoptotic transcription factor CHOP (GADD153) and down-regulation of B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, suggesting that inhibition of COX-2 sensitized human hepatoma cells to ER stress-induced apoptosis. Interestingly, co-treatment with tunicamycin and melatonin also decreased the expression of COX-2 and significantly increased the rate of apoptosis by elevating the levels of CHOP and reducing the Bcl-2/Bax ratio. These results demonstrate that melatonin sensitizes human hepatoma cells to ER stress-induced apoptosis by down-regulating COX-2 expression, increasing the levels of CHOP and decreasing the Bcl-2/Bax ratio.

According to the character of the trans-critical CO2cycle, this paper develops the theoretical model of the gas cooler using the distributed-parameter method. At last, it optimizes the gas cooler. The comparison between the simulation and the experiments indicates: under different inlet temperature of cooling water, high pressure and mass flux of the refrigerant, the maximum deviation between the simulation and the experimental results is 5.6%, 10.1% and 19.7%,respectively. The optimal results indicates: when the refrigerant inlet is 8MPa and 93°C，and the cooling water inlet is 15°C，it is propitious to the inner heat exchange of the gas cooler using the four pipes of φ6mm×1mm, and the total heat exchange area of 1.1 m2.

A new class of efficient low-molecular-weight gelators composed of a 2-substituted anthraquinone and a hydrazide subunit were synthesized, and the structure–property relationships with respect to their gelation abilities in organic solvents were investigated. The toluene gels showed exceptional thermal stability. Interestingly, it was also found that the ultrasound radiation could promote 1b–e to form a stable organogels instead of precipitates in polar solvent, and the ultrasound could remarkably induce changes of the morphology of the assembly in pyridine. Moreover, the reversible gel to sol phase transition could be achieved by adding TFA and TEA. The gelators 1b–e further showed selective gelation of aromatic solvents or chloroalkanes from their mixtures with water.

K2NiF4 type compounds Sm2-xSrxCuO4(0 ≤ x ≤ 1.2) were prepared. Rietveld refinement of powder diffraction data snows that the crystal system of these compounds belongs to T type tetragonal structure of space group I4/mmm, and the addition of Sr causes a dramatic shift of the O(I) ions along the c axis from Sm (Sr) toward Cu while scarcely affecting the Cu—O (II) bond in basal CuO4 plane. From XRD data, it can be seen that when 0.0 ≤ x ≤ 0.6, Sm2-xSrxCuO4 belongs to a single-phase K2NiF4 type structure, while at x ⩾ 0.7, both the free SrO phase and the CuO phase exist in these compounds. From the results of XPS and Rietveld refinement, it can be seen that after replacing Sm3+ with Sr2+ of lower valence, the valence of Cu and Sm does not change apparently, and thus some defect must be formed at the oxygen ion positions and/or position A on A2BO4 to keep charge balance and to stabilize the structure.

Two novel low-molecular-weight organogelators (LMOGs) 1 and 2 composed of an anthraquinone unit, a hydrazide group, and long alkyl chains were synthesized. They could form stable gels in wide tested solvents. Chloroalkanes and aromatic solvents tend to result in transparent gels, while alcohol and other solvents yield opaque gels. The FT-IR, PXRD, and (1)H NMR spectral studies revealed that hydrogen bonding and pi-pi interactions were the main driving forces for formation of the gels. Although the hydrazide unit and the anthraquinone group were connected by the sigma-bond, the chloroform gel of 1 could be changed into a red solution upon the addition of anion (F(-), AcO(-), and H(2)PO(4)(-)) due to the disruption of the intermolecular hydrogen-bondings. Moreover, the red color clearly faded at once and the solution regelated upon the addition of methanol. The results indicated that 1 and 2 as smart anion-responsive gel might provide the basis for the development of nonfluid systems for sensing anion with the naked eye.

Trichloroethylene (TCE), a major chemical hazard during occupational exposure, can cause obvious skin lesions, including irritant reactions and dermatitis. Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) is involved in a broad array of pathogenesis of skin inflammatory and immune responses. To understand the mechanisms of TCE-induced dermatoxicity, we investigated the effects of TCE on NO production and NOS mRNA expression in cultured normal human epidermal keratinocytes (NHEK). Cells were treated with TCE (0 mM, 0.125 mM, 0.25 mM, 0.5 mM, 1.0 mM, 2.0 mM) for 4 h, and then incubated for 12 h, 24 h, 48 h and 72 h. At each given time point, NO production were evaluated indirectly by measuring nitrite plus nitrate concentration in the culture medium using Griess reaction, as well as cell viability determined by MTT test, iNOS and cNOS activities assayed with a NOS activity detecting kit. The expression of iNOS and cNOS mRNA was detected using RT-PCR. TCE decreases cell viability and enhance NO production from NHEK in concentration- and time-dependent manner. Aminoguanidine (AG), an inhibitor of NOS, can prevent NO production and cell viability decrease in NHEK by TCE induced. Change to NO production was accompanied by increased activities of both types of NOS, but the iNOS activity accounted mainly for the TCE-induced NO production. RT-PCR detection showed that NHEK expressed both iNOS and cNOS mRNA by TCE exposure. Whereas a concentration- and time-dependent up-regulation of the mRNA expression was observed for iNOS and cNOS following TCE exposure, changes to iNOS were more marked. These results suggest that TCE caused increase in NO production, attributed to activation of iNOS as well as cNOS, and expression of iNOS and cNOS mRNA. These cellular changes may contribute to the pathological and physiological features of TCE-induced erythema and skin inflammation.

Bismuth (Bi)-containing SBA-15 mesoporous silica catalysts, Bi/SBA-15, with different Bi loadings were synthesized by a direct hydrothermal method. The materials were characterized in detail by various techniques. Powder-X-ray-diffraction (PXRD), N-2-adsorption/desorption, and transmission-electronmicroscopic (TEM) analyses revealed that the well-ordered hexagonal structure of SBA-15 is maintained after Bi incorporation. Diffuse-reflectance UV/VIS, Raman, and X-ray photoelectron spectroscopy (XPS) showed that the incorporated Bi-atoms are highly dispersed, most of them entering the internal surface of SBA-15. The new, very stable catalysts were found to be highly efficient for the oxidation of cyclohexane in a solvent-free system, molecular oxygen (02) being used as oxidant.

The trend toward the energy efficiency improvement for transcritical carbon dioxide refrigeration cycles has led to the development of the two-stage compression process. Three different variations of transcritical carbon dioxide two-stage compression cycles with expanders are investigated by using thermodynamics analysis. They are the two-stage compression at optimal intermediate pressure (TCOP) cycle, two-stage compression with expander driving high-pressure stage (TCDH) cycle and two-stage compression with expander driving low-pressure stage (TCDL) cycle, respectively. The performance of the TCOP cycle and the single-stage compression with expander (SCE) cycle is mainly discussed and compared for a wide operating condition. It is found that the COP and exergy efficiency of the TCOP cycle are on average 9% higher than those of the SCE cycle. At given design points, the COP of the TCDH cycle outperforms the other options, showing 11.32%, 9.65% and 0.72% performance improvement over the TCDL cycle, SCE cycle and the TCOP cycle, respectively. If design and structure are also taken into account, the TCDH cycle is a feasible option since the expander and the auxiliary compressor are integrated into one unit; thus, the transfer loss and leakage loss can be decreased greatly. The key problem is to adopt some measures that control the operating conditions to avoid deviating from the design point.

In this paper, a comparative study is performed for the transcritical carbon dioxide refrigeration cycles with a throttling valve and with an expander, based on the first and second laws of thermodynamics. The effects of evaporating temperature and outlet temperature of gas cooler on the optimal heat rejection pressure, the coefficients of performance (COP), the exergy losses, and the exergy efficiencies are investigated. In order to identify the amounts and locations of irreversibility within the two cycles, exergy analysis is employed to study the thermodynamics process in each component. It is found that in the throttling valve cycle, the largest exergy loss occurs in the throttling valve, about 38% of the total cycle irreversibility. In the expander cycle, the irreversibility mainly comes from the gas cooler and the compressor, approximately 38% and 35%, respectively. The COP and exergy efficiency of the expander cycle are on average 33% and 30% higher than those of the throttling valve cycle, respectively. It is also concluded that an optimal heat rejection pressure can be obtained for all the operating conditions to maximize the COP. The analysis results are of significance to provide theoretical basis for optimization design and operation control of the transcritical carbon dioxide cycle with an expander.

The syntheses of 2-(4-aminocarbonyl-2-thiazoyl)-1,4-anhydro-D-ribitol 10 and 2-(4-aminocarbonyl-2-thiazoyl)-1,4-anhydro-D-arabitol 11 have been accomplished via the construction of thiazoyl moiety from the cyanohydrins 2 and 3.

New Frechet-type dendritic BINOL ligands bearing several BINOL units at the periphery have been successfully synthesized. The (dendritic BINOL) Ti(IV) complexes were proved to be efficient catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes. Moreover, these ligands could be quantitatively recovered and reused at least five times without a loss of the yield and enantioselectivity.

Dianhydro-L-talofuranose dimethylacetal 7 was synthesized from D- glucose in 7 steps. A series of 4-deoxy-4-nucleobase-2,5-anhydro-L-mannitols 13-16 were synthesized regioselectively from 7 in good yields. 6-O-p-Tolylsulfonyl-2,5:3,4- dianhydro-L-talofuranose dimethylacetal 8 reacted with uracil or thymine to give the corresponding isonucleosides 17 and 19, but in the case of reaction of 8 with adenine, reformation of tetrahydrofuran ring took place, giving 4-(S)-adenyl-5-(R)-(l'-(R)-hydroxy- 2',2'-dimethoxy) ethyl-2,3-dihydrofuran 21 and 4-deoxy-4-adenyl-2,5:3,6-dianhydro-L- mannofuranose dimethylacetal 22. © 1997 Elsevier Science Ltd A number of nucleoside analogues have been found to possess anticancer and antiviral activities.l-4 In the search for effective, selective and nontoxic anticancer and antiviral agents, the discovery of a new class of nucleosides is of immense importance. Isonucleoside is a new class of nucleoside analogues in which the nucleobase is linked to a position of ribose other than C-1'. Therefore isonucleosides have attracted much attention owing to their chemical and enzymatic stability and potential antiviral activities. 5 A series of isomers of 2',3'-dideoxynucleosides which contain a modified carbohydrate moiety have been synthesized and some of these compounds exhibited significant and selective anti- HIV activity. 6,7 New regioisomers of AZT, AZU, BVDU and IDU have also been synthesized, s Recently, a number of nucleosides with the unnatural L-configuration have been reported as potent chemotherapeutic agents against HIV, HBV and certain forms of cancer. It is interesting that these L-nucleosides have potent biological activities, while some of them show lower toxicity profiles than their D-counterparts. 9 We have reported the synthesis of 4'-(R)-hydroxy-5'-(S)-hydroxymethyl- tetrahydrofuranyl purines and pyrimidines from D-xylose. 1° In this paper, we describe the synthesis of some derivatives of 4-deoxy-4-nucleobase-2,5-anhydro-L-mannitols from D-glucose. Many isonucleosides syntheses have been achieved by use of epoxide opening by an azide anion, with subsequent reduction furnishing an amino group which is used to build up a heterocyclic moiety. An alternative synthesis involves the substitution of a leaving group on the sugar ring by a heterocyclic nucleophile under basic conditions. In order to avoid lengthy synthetic routes, we synthesized isonucleosides by using an epoxide opening by a nucleobase itself in basic conditions. The desired epoxide can be obtained from a corresponding sugar. Our strategy for the synthesis of the epoxide required the leaving group and hydroxyl group in a trans relationship on the sugar moiety. The key intermediates 5 and 6 were synthesized from 1,2-O-isopropylidene-3,5-di-O-p-tolylsulfonyl-6-O- benzoyl-ot-D-glucofuranose 2 or 1,2-O-isopropylidene-3,5,6-tri-O-p-tolylsulfonyl-ot-D-glucofuranose 3, respectively, which in turn was prepared from D-glucose. 11 Results and discussion When 2 was treated with 2% TFA in methanol under reflux for 72 h, a mixture of ¢x- and (3-methyl- 3,5-di-O-p-tolylsulfonyl-6-O-benzoyl-D-glucofuranosides was obtained. We modified the procedure

Apoptosis resistance in hepatocellular carcinoma (HCC) is one of the most significant factors for hepatocarcinogenesis and tumor progression, and leads to resistance to conventional chemotherapy. It is well known that inhibitor of apoptosis proteins (IAPs) play key roles in apoptosis resistance, it has become an important target for antitumor therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, targeted IAPs, leading to the inhibition of apoptosis resistance. To accomplish this, we first observed that four members of IAPs (cIAP-1, cIAP-2, survivin, and XIAP) were overexpressed in human HCC tissue. Interestingly, melatonin significantly inhibited the growth of HepG2 and SMMC-7721 cells and promoted apoptosis along with the downregulation of survivin and XIAP, but had no effect on the expression of cIAP-1 and cIAP-2. These data suggest that the inhibition of survivin and XIAP by melatonin may play an important part in reversing apoptosis resistance. Notably, cIAP-1, survivin and XIAP were significantly associated with the coexpression of COX-2 in human HCC specimens. Melatonin also reduced the expression of COX-2 and inhibited AKT activation in HepG2 and SMMC-7721 cells. Inhibition of COX-2 activity with the selective inhibitor, NS398, and inhibition of AKT activation using the PI3K inhibitor, LY294002, in tumor cells confirmed that melatonin-induced apoptosis was COX-2/PI3K/AKT-dependent, suggesting that the COX-2/PI3K/AKT pathway plays a role in melatonin inhibition of IAPs. Taken together, these results suggest that melatonin overcomes apoptosis resistance by the suppressing survivin and XIAP via the COX-2/PI3K/AKT pathway in HCC cells.

Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress-induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC-7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co-pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p-AKT) was elevated in HepG2 and SMMC-7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP-homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the PI3K/AKT pathway by melatonin-reversed ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by down-regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin.

Dianhydro-L-talofuranose dimethylacetal 7 was synthesized from D- glucose in 7 steps. A series of 4-deoxy-4-nucleobase-2,5-anhydro-L-mannitols 13-16 were synthesized regioselectively from 7 in good yields. 6-O-p-Tolylsulfonyl-2,5:3,4- dianhydro-L-talofuranose dimethylacetal 8 reacted with uracil or thymine to give the corresponding isonucleosides 17 and 19, but in the case of reaction of 8 with adenine, reformation of tetrahydrofuran ring took place, giving 4-(S)-adenyl-5-(R)-(l'-(R)-hydroxy- 2',2'-dimethoxy) ethyl-2,3-dihydrofuran 21 and 4-deoxy-4-adenyl-2,5:3,6-dianhydro-L- mannofuranose dimethylacetal 22. © 1997 Elsevier Science Ltd A number of nucleoside analogues have been found to possess anticancer and antiviral activities.l-4 In the search for effective, selective and nontoxic anticancer and antiviral agents, the discovery of a new class of nucleosides is of immense importance. Isonucleoside is a new class of nucleoside analogues in which the nucleobase is linked to a position of ribose other than C-1'. Therefore isonucleosides have attracted much attention owing to their chemical and enzymatic stability and potential antiviral activities. 5 A series of isomers of 2',3'-dideoxynucleosides which contain a modified carbohydrate moiety have been synthesized and some of these compounds exhibited significant and selective anti- HIV activity. 6,7 New regioisomers of AZT, AZU, BVDU and IDU have also been synthesized, s Recently, a number of nucleosides with the unnatural L-configuration have been reported as potent chemotherapeutic agents against HIV, HBV and certain forms of cancer. It is interesting that these L-nucleosides have potent biological activities, while some of them show lower toxicity profiles than their D-counterparts. 9 We have reported the synthesis of 4'-(R)-hydroxy-5'-(S)-hydroxymethyl- tetrahydrofuranyl purines and pyrimidines from D-xylose. 1° In this paper, we describe the synthesis of some derivatives of 4-deoxy-4-nucleobase-2,5-anhydro-L-mannitols from D-glucose. Many isonucleosides syntheses have been achieved by use of epoxide opening by an azide anion, with subsequent reduction furnishing an amino group which is used to build up a heterocyclic moiety. An alternative synthesis involves the substitution of a leaving group on the sugar ring by a heterocyclic nucleophile under basic conditions. In order to avoid lengthy synthetic routes, we synthesized isonucleosides by using an epoxide opening by a nucleobase itself in basic conditions. The desired epoxide can be obtained from a corresponding sugar. Our strategy for the synthesis of the epoxide required the leaving group and hydroxyl group in a trans relationship on the sugar moiety. The key intermediates 5 and 6 were synthesized from 1,2-O-isopropylidene-3,5-di-O-p-tolylsulfonyl-6-O- benzoyl-ot-D-glucofuranose 2 or 1,2-O-isopropylidene-3,5,6-tri-O-p-tolylsulfonyl-ot-D-glucofuranose 3, respectively, which in turn was prepared from D-glucose. 11 Results and discussion When 2 was treated with 2% TFA in methanol under reflux for 72 h, a mixture of ¢x- and (3-methyl- 3,5-di-O-p-tolylsulfonyl-6-O-benzoyl-D-glucofuranosides was obtained. We modified the procedure

The syntheses of 2-(4-aminocarbonyl-2-thiazoyl)-1,4-anhydro-D-ribitol 10 and 2-(4-aminocarbonyl-2-thiazoyl)-1,4-anhydro-D-arabitol 11 have been accomplished via the construction of thiazoyl moiety from the cyanohydrins 2 and 3.

New Frechet-type dendritic BINOL ligands bearing several BINOL units at the periphery have been successfully synthesized. The (dendritic BINOL) Ti(IV) complexes were proved to be efficient catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes. Moreover, these ligands could be quantitatively recovered and reused at least five times without a loss of the yield and enantioselectivity.

Multilayer films of oligo(pyrenebutyric acid) (OPB) and N,N'-bis(N,N-dimethylaminopropylaminopropyl)-3,4,9,10-perylenediimide (BDMAPAP-PDI) were successfully fabricated by layer-by-layer deposition. Multilayer growth was monitored by ultraviolet-visible (UV-vis) spectroscopy, fluorescence spectroscopy, ellipsometry, and atomic force microscopy (AFM). It was found that extraction was scarcely observed although both components (OPB and BDMAPAP-PDI) have low molecular weights and both electrostatic interactions and pi-pi stacking contributed to the multilayer deposition. The multilayers exhibit a rapid photocurrent response, and excitations of both OPB and BDMAPAP-PDI can lead to the effective charge dissociation. The incident photon to current conversion efficiency (IPCE) of the composite film with 5 bilayers was measured to be 1.29% at the absorption peak of BDMAPAP-PDI. Fluorescence quenching and photovoltaic conversion studies indicated that strong photoinduced charge transfer interactions occurred at the area of OPB/BDMAPAP-PDI heterojunction in the films, which strongly enhanced the photoresponse of the multilayer films.

Hotien county in Xinjiang province, China, is an area of severe iodine deficiency and has a high infantmortality rate. We investigated whether iodine replacement through iodination of the irrigation water would decrease infant mortality.We added potassium iodate to irrigation water over a 2 to 4 week period beginning in 1992 in certain areas of three townships (Tusala, Long Ru, and Bakechi). Logistic regression analysis was used to compare the odds ratios for infant and neonatal mortality in treated and intreated areas.The median urinary iodine concentration significantly increased in women of child-bearing age from10 micrograms/L to 55 micrograms/L. Infant-mortality rates decreased in the treated areas of Long Ru (mean [SD] 58.2 [4.4] per 1000 births to 28.7 [7.1] per 1000 births), Tusala (47.4 [12.4] per 1000 births to 19.1 [1.5] per 1000 births), and Bakechi (106.2 [9.5] per 1000 births to 57.3 [7.3] per 1000 births). Similar results were also seen for neonatal mortality. On regression analysis iodine treatment and time were significant independent predictors of infant mortality.Iodine supplementation of irrigation water in areas of severe iodine deficiency decreases neonatal and infant mortality. Iodine replacement has probably been an important factor in the national decrease in infant mortality in China.Hotien county in Xinjiang province is an area of severe iodine deficiency which also has a high infant mortality rate (IMR). The authors investigated whether iodine replacement through iodination of irrigation water would decrease the level of infant mortality. Potassium iodine was added to irrigation water over a 2-4 week period beginning in 1992 in certain areas of Long Ru, Tusala, and Bakechi. The median urinary iodine concentration significantly increased in women of child-bearing age from less than 10 mg/l to 55 mg/l, while IMR decreased in Long Ru from a mean of 58.2/1000 births to 28.7/1000, in Tusala from 47.4/1000 to 19.1/1000, and in Bakechi from 106.2/1000 to 57.3/1000. Similar results were also observed for neonatal mortality. Iodine treatment and time were significant independent predictors of infant mortality.

Background Endoplasmic reticulum stress (ER stress) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone), is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress–induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC) are poorly understood. Methodology/Principal Findings In this study, we investigated the effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM) before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153) in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. Conclusions/Significance Our results demonstrate that Pae reverses ER stress–induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.

A series of 4′-(R)-hydroxy-5′-(S)-hydroxymethyl-tetrahydrofuranyl purines and pyrimidines were synthesized by the reaction of 3,4-epoxy-5-(S,trans)-dimethoxymethyl-tetrahydrofuran and nucleobases under the catalysis of potassium tert-butoxide and 18-crown-6. Compounds 6a, 6c and 7b have shown significant inhibition on the growth of HL-60 cells. The phosphotriester and phosphodiester of isonucleoside 8a-d were synthesized and cytotoxic activities were reported. The conformation of isonucleosides in solution was studied by 1H NMR.