Optical nondegenerate solitons in a birefringent fiber with a 35 degree elliptical angle.

In this paper, we investigate the optical nondegenerate solitons in a birefringent fiber with a 35 degree elliptical angle. We derive the nondegenerate bright one- and two-soliton solutions by solving the coupled Schrödinger equation. The formation of nondegenerate solitons is related to the wave numbers of the solitons, and we further demonstrate that it is caused by the incoherent addition of different components. We note that the interaction between two degenerate solitons or a nondegenerate soliton and a degenerate soliton is usually inelastic. This is led to the incoherent interaction between solitons of different components and the coherent interaction between solitons of the same component. Through the asymptotic analysis, we find that the two degenerate solitons are elastic interactions under certain conditions, and analyzed the influence of the Kerr nonlinear intensity coefficient γ and the second-order group velocity dispersion ß2 in this system on solitons: the velocity and amplitude of the solitons are proportional to |ß2|, while the amplitude of the solitons is inversely proportional to γ. Two nondegenerate solitons are elastic interactions, but the phase of the soliton can be adjusted to make it inelastic. Furthermore, regardless of the situation mentioned above, total intensities of the solitons before the interaction are equal to that after the soliton interaction.

Taicrypnacids A and B, a Pair of C37 Heterodimeric Diterpenoid Stereoisomers from Taiwania cryptomerioides.

Two uncommon C37 heterodimeric diterpenoids, taicrypnacids A (1) and B (2), and a known labdane-type diterpenoid (3) were isolated from the leaves of Taiwania cryptomerioides. Several techniques, such as comprehensive spectroscopic analysis, chemical conversion, X-ray crystallography, and ECD data, were employed to define the structures. The two new compounds displayed cytotoxicity against human breast cancer (MCF-7), osteosarcoma (U-2 OS), and human colon carcinoma (HCT-116) cell lines, while the methyl ester 1a showed no activity. Compound 1 induced Ca2+-ROS pathway-mediated endoplasmic reticulum stress, and excessive stress led to cell death by activating apoptosis and autophagy.

Pharmacokinetics Evaluation of Mycophenolic Acid and Its Glucuronide Metabolite in Chinese Renal Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium and Tacrolimus.

BACKGROUND: The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination. METHODS: Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis. RESULTS: Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%. CONCLUSIONS: The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.

Taiwanoids A-D, four dimeric diterpenoids featuring tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane from Taiwania cryptomerioidesim.

Biogenesis-inspired chemical research of the leaves of Taiwania cryptomerioides afforded four unprecedented dimeric diterpenes, featuring a tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane core: taiwanoids A-D (1-4). The structures of these compounds were determined on the basis of comprehensive spectral analysis, chemical conversions and X-ray crystallography. A possible biosynthetic pathway for compounds 1-4 was proposed. Compounds 2 and 3 exerted a 5.37 and 6.26-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration of 20 µM, respectively.

Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation.

Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by clitocine. In fact, more ubiquitinated Mcl-1 was detected under clitocine treatment. Our findings indicate that clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.

[The determination and clinical application of inosine 5'-monophosphate dehydrogenase activity].

Inosine 5'-monophosphate dehydrogenase(IMPDH) is a rate-limiting enzyme in de novo biosynthesis of guanine and plays an important role in cell proliferation. In clinic, IMPDH inhibitors are mainly used in fields of anticancer, antiviral, anti-parasitic, and immunosuppressive chemotherapy. However, since there are usually great inter- and intra-individual variability between drug concentration and clinical effect of IMPDH inhibitors, the enzyme activity of IMPDH may be applied as a specific biomarker and combined with the pharmacokinetics (PK) monitoring to improve efficacy and safety of IMPDH inhibitors. This review aims to discuss the assay of IMPDH activity measurement and its clinical application in recent years and provide valuable insights and theoretical basis for the development of IMPDH inhibitors' pharmacodynamics monitoring.

Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo.

Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.

Anticancer effects of imperatorin isolated from Angelica dahurica: induction of apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways.

BACKGROUND: Imperatorin (IM) is a furanocoumarin isolated from the root of Angelica dahurica, which is reported to have anticonvulsant and anticancer effects. In this study, the antiproliferative effect of IM on 9 human cancer cell lines was examined, and human hepatoma HepG2 cells were chosen as the target for preferential killing by IM. Particularly, the mechanism of IM-induced apoptosis and in vivo animal effects were also studied. METHODS: Cell viability was measured using MTT assay, and apoptosis was detected by Hoechst staining, annexin V-PI staining, and DNA laddering assay. Mitochondrial membrane potential was detected by JC-1 staining. Western blot analysis was employed to detect the expression of apoptosis-related proteins. In addition, the in vivo anticancer effect of IM was examined in nude mice bearing HepG2 cells. RESULTS: IM inhibited the proliferation of HepG2 cells through apoptosis induction in a time- and dose-dependent manner by observation of the nuclear morphology, DNA fragmentation, phosphatidylserine externalization, loss of mitochondrial membrane potential, release of cytochrome c into cytosol, and activation of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase cleavage. As cell death could partly be prevented by the caspase-8 or caspase-9 inhibitor and was evidenced by the results of Western blot analysis, our results also suggest that IM-induced apoptosis is mediated through both death receptor and mitochondrial pathways. In the animal model, IM was found to effectively suppress tumor growth by 31.93 and 63.18% at dosages of 50 and 100 mg/kg, respectively, after treatment for 14 days. No significant weight loss or toxicity to the hosts was found. CONCLUSIONS: IM can function as a cancer suppressor by inducing apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways. Furthermore, the in vivo antitumor activities of IM are significant with negligible weight loss and damage to the host.

3,5-Dimethyl-H-furo[3,2-g]chromen-7-one as a potential anticancer drug by inducing p53-dependent apoptosis in human hepatoma HepG2 cells.

BACKGROUND/AIMS: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. METHOD: Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. RESULT: Among the 6 derivatives, 3,5-dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC(50) value of 8.46 ± 0.28 µM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. CONCLUSION: DMFC is potentially an effective therapeutic agent in liver cancer therapy.

Synthesis and antiproliferative activities of novel 5'-Schiff-base group substituted psoralen derivatives.

It was found that psoralen derivative could perform a Friedel-Crafts acylation smoothly with acetic anhydride to give 5'-acetylpsoralen in a 73% yield. In the presence of boron trifluoride etherate, 5'-acetylpsoralen reacted with both aromatic amines and aliphatic amine smoothly to afford 5'-Schiff-base group substituted psoralen derivatives in 72%-92% yields. The novel synthetic method has the advantages of cheap materials, mild reaction conditions, good yields and high regioselectivity in the Friedel-Crafts acylation. Cell viability assay by MTT demonstrates that some of the psoralen derivatives 6 have antiproliferative activities.

Influence of protein type, content and polymerization on in vitro starch digestibility of sorghum noodles.

The impacts of protein type, content and polymerization on in vitro starch digestibility of cooked sorghum noodles were investigated. Results showed that addition of exogenous proteins decreased the starch hydrolysis rate. The noodles added wheat protein (WP) exhibited the highest amount of resistant starch, followed by whey protein isolate (WPI) and egg white protein (EWP). In each group, the hydrolysis kinetic parameters were the lowest when protein addition amounts were 5% WP, 3% EWP and 3% WPI, respectively. These changes were ascribed to the interactions of starch-proteins and protein-proteins, as proved by the enhancement of protein polymerization and starch short-range structure. The increase of protein polymerization degree induced by disulfide cross-links reduced the starch digestion rate of noodles. Additionally, the confocal laser scanning microscope observations demonstrated that the strengthening of protein network had a positive effect on decreasing starch digestibility by preventing the accessibility of enzymes to starch.

Effect of thermal treatments on in vitro starch digestibility of sorghum dried noodles.

In this paper, sorghum grains were pretreated by roasting (RT), microwave (MW), stir-frying (SF) and heat-moisture treatment (HMT). The effects of pretreated sorghum grains on in vitro starch digestibility of sorghum dried noodles made from sorghum and wheat flour were investigated. The results showed that HMT treated noodles contained the highest amount of resistant starch (RS) and the lowest amount of rapidly digestible starch (RDS). The hydrolysis kinetic parameters and estimated glycemic index (eGI) decreased in all of the treated samples. The treated starches had lower molecular weight and less proportion of short chains of amylopectin than those of the untreated sample. X-ray diffraction demonstrated that the relative crystallinity of starch in noodles was increased by HMT and RT treatments while it was decreased by MW and SF treatments compared to untreated noodles. Fourier transform infrared (FTIR) analysis revealed that the short-range ordered degree and intra-molecular hydrogen bond intensity were both enhanced by thermal treatments. A tighter and smoother microstructure with fewer pores and cracks in the treated noodles was observed by scanning electron microscopy (SEM). These structural changes could provide a better understanding of the lower starch digestion rate.

Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met.

Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Alk (containing parasitic fungi Hypomyces hyalines (Schw.) Tul.). Here, we initially found, by wound healing assay and Transwell assay in vitro, that verticillin A possesses an inhibitory effect against the migration and invasion of the human colon cancer cell. Subsequently, c-mesenchymal-epithelial transition factor (c-Met) was identified as a molecular target of verticillin A by screening key genes related to cell migration. Verticillin A-mediated c-Met suppression is at the transcriptional level. Further study demonstrated that verticillin A suppressed c-MET phosphorylation and decreased c-MET protein level. In addition, verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma (Ras)-associated factor (Raf), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell. More importantly, verticillin A also inhibited cancer cell metastasis in vivo. Thus, verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase (MEK)/ERK signaling pathways. Therefore, we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.

Chocolate consumption and risk of cardiovascular diseases: a meta-analysis of prospective studies.

OBJECTIVE: Studies investigating the impact of chocolate consumption on cardiovascular disease (CVD) have reached inconsistent conclusions. As such, a quantitative assessment of the dose-response association between chocolate consumption and incident CVD has not been reported. We performed a systematic review and meta-analysis of studies assessing the risk of CVD with chocolate consumption. METHODS: PubMed and EMBASE databases were searched for articles published up to 6 June 2018. Restricted cubic splines were used to model the dose-response association. RESULTS: Fourteen publications (23 studies including 405 304 participants and 35 093 cases of CVD) were included in the meta-analysis. The summary of relative risk (RR) per 20 g/week increase in chocolate consumption was 0.982 (95% CI 0.972 to 0.992, I2=50.4%, n=18) for CVD (heart failure: 0.995 (0.981 to 1.010, I2=36.3%, n=5); total stroke: 0.956 (0.932 to 0.980, I2=25.5%, n=7); cerebral infarction: 0.952 (0.917 to 0.988, I2=0.0%, n=4); haemorrhagic stroke: 0.931 (0.871 to 0.994, I2=0.0%, n=4); myocardial infarction: 0.981 (0.964 to 0.997, I2=0.0%, n=3); coronary heart disease: 0.986 (0.973 to 0.999, n=1)). A non-linear dose-response (pnon-linearity=0.001) indicated that the most appropriate dose of chocolate consumption for reducing risk of CVD was 45 g/week (RR 0.890;95%CI 0.849 to 0.932). CONCLUSIONS: Chocolate consumption may be associated with reduced risk of CVD at <100 g/week consumption. Higher levels may negate the health benefits and induce adverse effects associated with high sugar consumption.

Cloning and characterization of a glucose 6-phosphate/phosphate translocator from Oryza sativa.

Plastids of nongreen tissues import carbon as a source of biosynthetic pathways and energy, and glucose 6-phosphate is the preferred hexose phosphate taken up by nongreen plastids. A cDNA clone encoding glucose 6-phosphate/phosphate translocator (GPT) was isolated from a cDNA library of immature seeds of rice and named as OsGPT. The cDNA has one uninterrupted open reading frame encoding a 42 kDa polypeptide possessing transit peptide consisting of 70 amino acid residues. The OsGPT gene maps on chromosome 8 of rice and is linked to the quantitative trait locus for 1000-grain weight. The expression of OsCPT is mainly restricted to heterotrophic tissues. These results suggest that glucose 6-phosphate imported via GPT can be used for starch biosynthesis in rice nongreen plastids.

Comparative mapping of QTLs for Al tolerance in rice and identification of positional Al-induced genes.

Aluminum (Al) toxicity is the major factor limiting crop productivity in acid soils. In this study, a recombinant inbreed line (RIL) population derived from a cross between an Al sensitive lowland indica rice variety IR1552 and an Al tolerant upland japonica rice variety Azucena, was used for mapping quantitative trait loci (QTLs) for Al tolerance. Three QTLs for relative root length (RRL) were detected on chromosome 1, 9, 12, respectively, and 1 QTL for root length under Al stress is identical on chromosome 1 after one week and two weeks stress. Comparison of QTLs on chromosome 1 from different studies indicated an identical interval between C86 and RZ801 with gene(s) for Al tolerance. This interval provides an important start point for isolating genes responsible for Al tolerance and understanding the genetic nature of Al tolerance in rice. Four Al induced ESTs located in this interval were screened by reverse Northern analysis and confirmed by Northern analysis. They would be candidate genes for the QTL.

Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak.

ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT-737. At the present study, we observed that clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of clitocine and ABT-737. Finally, clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis.

Suillin from the mushroom Suillus placidus as potent apoptosis inducer in human hepatoma HepG2 cells.

During the search of new anti-cancer agent from high fungi, the ethyl acetate extract of the mushroom Suillus placidus was found to exhibit a significant cytotoxic activity against human hepatoma HepG2 cells. With bioassay-guided fractionation, a cytotoxic component suillin was isolated from the extract. The anti-cancer effect of suillin was subsequently examined in 8 human cancer cell lines by using MTT assay. It is of interest to note that human liver cancer cells (HepG2 cells, Hep3B cells, and SK-Hep-1) were preferentially killed by suillin with an IC(50) of approximately 2microM in a 48h treatment. Mechanistically. suillin was found for the first time to induce apoptosis in HepG2 cells as characterized by DNA fragmentation, phosphatidyl-serine (PS) externalization, activation of caspase-3, -8, -9, depolarization of mitochondrial membrane potential, as well as release of cytochrome c into the cytosol. Moreover, the apoptosis induced by suillin was suppressed by both caspase-8 and -9 inhibitors. Western blot analysis revealed significant increases in the protein levels of Fas death receptor, adaptor FADD protein, pro-apoptotic protein Bad and a decline of Bid. These results suggest that the induction of apoptosis by suillin is through both death receptor and mitochondrial pathways. Taken together, our results suggest that suillin might be an effective agent to treat liver cancer.