Objective: To investigate the effect of glutamine (Gln) on pro-inflammatory cytokines (TNF-α, IL-2 and IL-10) and the balance between pro-inflammatory cytokines and anti-inflammatory cytokines in severe acute pancreatitis (SAP) rats receiving nutritional support in different ways. Methods: Male SD rats (n=80) were randomly assigned into 5 groups: sham group, SAP+ parenteral nutrition (PN) group, SAP+ enteral nutrition (EN) group, SAP+EN+Gln group and SAP+PN+Gln group. At the same time, rats in 5 groups were sacrificed at 4 and 7 days after nutritional support. ELISA was employed to detect the pro-inflammatory cytokines including TNF-α, IL-2 and IL-10. Results: The serum TNF-α in the EN+Gln group after 7-day treatment was significantly lower than that in the EN, PN and PN+Gln groups at corresponding time point (P<0.05). The serum IL-2 in the EN+Gln group after 7-day treatment was markedly higher than that in the EN, PN and PN+Gln groups at corresponding time point (P<0.01). After 7-day treatment, the serum IL-2 in the EN+Gln and EN groups were markedly higher than that after 4-day treatment (P<0.01), but the serum IL-2 in the PN group was significantly lower than that after 4-day treatment (P<0.01). The serum IL-10 after 7-day treatment was markedly lower than that after 4-day treatment in all groups (P<0.01), and PN group had the lowest serum IL-10. Serum IL-10 in the EN+Gln group was significantly higher than that in the PN and PN+Gln groups at both time points (P<0.01). The serum IL-10 in the EN group was significantly higher than that in the PN group after 4-day treatment (P<0.01), but the serum IL-10 in the EN group was comparable to that in the PN group after 7-day treatment. The serum IL-10/TNF-α in the EN+Gln group was only slightly higher than that in the control group at both time points. The serum IL-10/TNF-α in the EN group was significantly lower than that in the EN+Gln group at both time points (P<0.05). The serum IL-10/TNF-α in the PN group was markedly lower than that in the EN group and EN+Gln group (P<0.05 and P<0.01, respectively).Conclusion: EN in combination with Gln are superior to EN alone, PN alone and PN in combination with Gln in regulating inflammation in SAP rats, and the EN has more potent capability to regulate the balance between pro-inflammation and anti-inflammation than PN.
Pancreatitis; glutamine; inflammatory cytokines; rat
Some recent clinical reports have shown that the combination of oxymatrine, a phyto-derived drug, with lamivudine (3TC) could improve its curative effect against hepatitis B virus (HBV) infection. However, the experimental data in support of this combination strategy are lacking. In this study, we investigated the anti-HBV activity of the combination of 3TC and either oxymatrine or matrine on HepG2 2.2.15 in vitro. The activities of the combination and the solo compound, each in different concentrations, were compared on the 3rd, 6th, and 9th experimental days. The cytotoxicity results showed that the nontoxic concentrations of both oxymatrine and matrine to HepG2 2.2.15 cells were 800 μg/mL. We found that the single use of oxymatrine below 100 μg/ml, matrine below 200 μg/ml, and 3TC below 30 μg/ml showed weak inhibitory effects on the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV-DNA in culture media; the combination of 3TC (30 μg/ml) with oxymatrine (100 μg/ml) or matrine (100 μg/ml) showed significant inhibitory effects that were higher than or equivalent to the single use of 3TC at 100 μg/ml. The results provide a new impetus to develop novel, multicomponent anti-HBV drugs through the combination of natural products with nucleoside analogs to enhance their activity.
Doxorubicin (DOX) is one of the most effective cytotoxic anticancer drugs used for the treatment of hematological malignancies, as well as a broad range of solid tumors. However, the clinical applications of this drug have long been limited due to its severe dose-dependent toxicities. Therefore, DOX derivatives and analogs have been developed to address this issue. A type of DOX prodrug, cleaved by cathepsin B (Cat B), which is highly upregulated in malignant tumors and premalignant lesions, has been developed to achieve a higher DOX concentration in tumor tissue and a lower concentration in normal tissue, so as to enhance the efficacy and reduce toxicity to normal cells. In this review, we focused on Cat B-cleavable DOX prodrugs and discussed the efficacy of these prodrugs, demonstrated by preclinical and clinical developments.
cancer chemotherapy; cathepsin B; doxorubicin; prodrugs; targeted therapy
To test the hypothesis that a combination of PP13, PAPP-A and first-trimester uterine artery Doppler would improve the prediction of preeclampsia.
This is a prospective cohort study of pregnant women followed from the first-trimester to delivery. PP13 and PAPPA were determined by immunoassay of maternal serum at 11 – 14 weeks’, when uterine artery Doppler measurements were assessed. Cases identified with any form of preeclampsiawere compared with a control group without preeclampsia. The sensitivity of each marker or their combinations in predicting preeclampsia for different fixed false positive rates was calculated from the ROC curves.
Forty two women were diagnosed with preeclampsia and 410 women with pregnancies not complicated by preeclampsia were used as controls. For a fixed false positive rate (FPR) of 20%, PP13, PAPP-A and mean uterine artery pulsatility index identified 49%, 58% and 62% respectively, of women who developed any form of preeclampsia. PP13 was best in predicting early onset preeclampsia with a sensitivity of 79% at a 20% FPR.Combinations of the three first trimester assessments did not improve the prediction of preeclampsia in later pregnancy.
First-trimester PP13, PAPP-A and uterine artery PI are reasonable, individual predictors of women at risk to develop preeclampsia. Combinations of these assessments do not further improve the prediction of preeclampsia
PAPP-A; PP13; Uterine artery; Preeclampsia; Prediction
Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydro-phenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case–control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00–2.88), 1.07 (0.62–1.84), 1.48 (0.86–2.53), and 2.34 (1.33–4.11), respectively, relative to the lowest quartile (Ptrend = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.
Our previous studies had shown that DAZAP2 was profoundly downregulated in bone marrow mononuclear cells from multiple myeloma patients. In this report, we analyzed epigenetic changes in multiple myeloma cell lines to understand the molecular mechanisms underlying the downregulation of DAZAP2. Four multiple myeloma cell lines, KM3, MM.1S, OPM-2 and ARH-77, were studied. The results of methylation specific PCR (MSP) showed that the promoter of DAZAP2 was methylated for KM3, MM.1S, OPM-2 and unmethylated for ARH-77. The DAZAP2 promoter region was amplified to obtain a series of different length sequences. All of the amplified sequences were inserted to luciferase reporter vector. The constructs were transfected into COS-7 cells and the luciferase activities were measured to search for the core region of DAZAP2 promoter. Two CpG islands were found in DAZAP2 promoter region. The results of luciferase assay showed that CpG island 1 displayed weak transcriptional activity, whereas CpG island 2 exhibited strong transcriptional activity (273 folds) compared to the control. The sequence that covered both CpG islands 1 and 2 showed higher activity (1,734 folds) compared to the control, suggesting that the two islands had synergistic effect on regulating DAZAP2 expression. We also found that M. Sss I methylase could inhibit the luciferase activity, whereas demethylation using 5-aza-2′-deoxycytidine treatment rescued the expression of DAZAP2 for multiple myeloma cell lines. These data revealed that methylation of DAZAP2 promoter was involved in downregulation of DAZAP2 in multiple myeloma cells.
Gene presence/absence (P/A) polymorphisms are commonly observed in plants and are important in individual adaptation and species differentiation. Detecting their abundance, distribution and variation among individuals would help to understand the role played by these polymorphisms in a given species. The recently sequenced 80 Arabidopsis genomes provide an opportunity to address these questions.
By systematically investigating these accessions, we identified 2,407 P/A genes (or 8.9%) absent in one or more genomes, averaging 444 absent genes per accession. 50.6% of P/A genes belonged to multi-copy gene families, or 31.0% to clustered genes. However, the highest proportion of P/A genes, outnumbered in singleton genes, was observed in the regions near centromeres. In addition, a significant correlation was observed between the P/A gene frequency among the 80 accessions and the diversity level at P/A loci. Furthermore, the proportion of P/A genes was different among functional gene categories. Finally, a P/A gene tree showed a diversified population structure in the worldwide Arabidopsis accessions.
An estimate of P/A genes and their frequency distribution in the worldwide Arabidopsis accessions was obtained. Our results suggest that there are diverse mechanisms to generate or maintain P/A genes, by which individuals and functionally different genes can selectively maintain P/A polymorphisms for a specific adaptation.
In the title molecule, C29H28F2N2O, the piperazine ring adopts a chair conformation with the pendant N—C bonds in equatorial orientations. The conformation of the N—C—C—O linkage is gauche [torsion angle = −64.6 (4)°] and the dihedral angle between the fluorobenzene rings is 64.02 (15)°.
In the title compound, C28H28F2N2O2, the piperazine ring has a chair conformation with the pendant N—C bonds in equatorial orientations. The C=C double bond has an E conformation and the dihedral angle between the fluorobenzene rings is 70.8 (3)°. In the crystal, molecules are linked by C—H⋯O and C—H⋯F hydrogen bonds.
In the molecule of the title compound, C31H36N2O5, the piperazine ring displays a chair conformation. The dihedral angle between the benzene rings of the bis(4-methoxyphenyl)methyl group is 83.42 (15)°. In the crystal, centrosymmetrically related molecules are linked through pairs of C—H⋯O hydrogen bonds into dimers, generating an R
2(10) ring motif. The dimers are further connected into chains parallel to [2-10] by C—H⋯O hydrogen bonds involving the methoxy groups.
In the title molecule, C26H28F2N2O, the piperazine ring adopts a chair conformation, with the N-bonded substituents in equatorial orientations. The dihedral angle between the fluorobenzene rings is 69.10 (15).
Polycyclic aromatic hydrocarbons (PAH) are well established carcinogens that are likely to play a role in causing some human cancers. One accepted pathway of PAH metabolic activation is formation of bay region diol epoxides. Some individuals may be particularly susceptible to PAH carcinogenesis because they metabolically activate PAH more effectively than others. We have used measurement of urinary phenanthrene tetraols (Phe-tetraols) as a biomarker of PAH exposure plus metabolic activation, since bay region diol epoxides are hydrolyzed to tetraols. Because of stereoselectivity in Phe metabolism, Phe-(1R,2S,3R,4S)-tetraol (4) results mainly from the bay region diol epoxide pathway and Phe-(1S,2R,3S,4R)-tetraol (7) is formed mainly from the reverse diol epoxide pathway, not generally associated with carcinogenicity. The latter pathway accounts for more than 95% of human urinary Phe-tetraol. In most previous studies, Phe-tetraol was quantified without enantiomeric resolution, using a relatively rapid and practical method, applicable to large studies. It was not clear however whether measurement of overall unresolved Phe-tetraol would accurately represent the bay region diol epoxide metabolic activation pathway. Therefore, in this study we specifically quantified Phe-(1R,2S,3R,4S)-tetraol (4) by supplementing our usual analysis with chiral HPLC separations, and using [13C6]Phe-(1R,2S,3R,4S)-tetraol as internal standard. We then investigated the relationship of urinary levels of 4 to those of Phe-tetraols (4 + 7), quantified without enantiomeric resolution. We applied these methods to urine samples from cigarette smokers and highly PAH-exposed creosote workers. The results were also compared to levels of benzo[a]pyrene-7,8,9,10-tetraol and 1-hydroxypyrene in the same samples. Levels of 4 were highly correlated with those of 4 + 7 (r > 0.9, P<0.0001) in both types of urine samples. Strong correlations of 4 and 4 + 7 with benzo[a]pyrene-7,8,9,10-tetraol and 1-hydroxypyrene were also observed. The results of this study demonstrate therefore that practical and convenient measurement of overall Phe-tetraols (4 + 7) in human urine, without enantiomeric resolution, is an excellent indicator of PAH exposure and metabolism by the bay region diol epoxide metabolic activation pathway.
phenanthrene tetraol; benzo[a]pyrene tetraol; 1-hydroxypyrene; polycyclic aromatic hydrocarbon urinary metabolites
Polycyclic aromatic hydrocarbons (PAH) are among the likely major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step sequence resulting in the formation of diol epoxides which react with DNA producing adducts that can cause mutations and initiate the carcinogenic process. However, no previous published studies have examined this critical pathway in humans specifically exposed to PAH by inhalation of cigarette smoke. We used a unique approach employing a stable isotope derivative of phenanthrene, the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Twelve subjects each smoked a cigarette to which [D10]phenanthrene had been added. Plasma was analyzed for [D10]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D10]PheT), the major end product of the diol epoxide metabolism pathway of phenanthrene. The analysis was performed by gas chromatography-negative ion chemical ionization-tandem mass spectrometry, using [13C6]PheT as internal standard. The results demonstrated that the three-step pathway resulting in formation of diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity. Levels of [D10]PheT in plasma of all subjects were maximal at the earliest time points examined, 15–30 min after smoking the cigarette containing [D10]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Since PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking which should serve as a major warning to anyone contemplating initiating tobacco use.
cigarette smoking; polycyclic aromatic compounds; diol epoxides
There are two crystallographically independent molecules in the asymmetric unit of the title compound, C29H30N2O5, each having an E conformation about the C=C double bond. The dihedral angles between the methoxybenzene rings in the two molecules are 71.39 (17) and 68.64 (17)°. In the crystal, molecules are linked by C—H⋯O interactions.
In the title compound, C28H28Br2N2O2, the C=C double bond has an E configuration and the piperazine ring has a chair conformation, with the N—C bonds in equatorial orientations. The dihedral angle between the bromobenzene rings is 83.1 (4)°. In the crystal, molecules are linked by C—H⋯O and C—H⋯Br hydrogen bonds.
In the title compound, C27H26Br2N2O, the piperazine ring adopts a chair conformation with the N—C bonds in equatorial orientations. The C=C double bond has an E configuration. The dihedral angle between the bromobenzene rings is 83.0 (4)°. In the crystal, inversion dimers linked through pairs of C—H⋯O hydrogen bonds generate R
Polycyclic aromatic hydrocarbons (PAH) are believed to be causative agents for various types of cancers in humans. Benzo[a]pyrene (BaP) is a prototypic carcinogenic PAH, which requires metabolic activation to elicit its detrimental effects. The major end product of its diol epoxide metabolic activation pathway is r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (trans, anti-BaPT). Individual differences in exposure to, and metabolic activation of, carcinogenic PAH may influence cancer risk. Measurement of PAH metabolites in human urine could provide a direct way to assess individual differences in susceptibility to PAH-related cancer. In this paper, we describe a sensitive and reliable method for quantitation of trans, anti-BaPT in human urine using gas chromatography-negative ion chemical ionization-tandem mass spectrometry (GC-NICI-MS/MS). [13C6] trans, anti-BaPT was used as the internal standard. The urine was treated with β-glucuronidase and sulfatase, and then trans, anti-BaPT was enriched by solid-phase extraction with polymeric reversed phase and phenylboronic acid cartridges. The sample was silylated and analyzed by GC-NICI-MS/MS with selected reaction monitoring (SRM) for the trimethylsilyl (TMS) derivatives of trans, anti-BaPT (m/z 446→ m/z 255) and [13C6]trans, anti-BaPT (m/z 452→ m/z 261). The mean assay recovery was 44%. The instrumental on-column detection limit was about 20 amol of trans, anti-BaPT (as BaPT-TMS). trans, anti-BaPT was readily detected in all urine samples analyzed including 30 smokers (0.71 ± 0.64 fmol/mg creatinine) and 30 non-smokers (0.34 ± 0.2 fmol/mg creatinine) (P = 0.0018). The results of this study demonstrate a highly sensitive and selective method for quantitation of trans, anti-BaPT in human urine. This is to our knowledge the first study to show that smokers have significantly higher levels of trans, anti-BaPT in their urine than do non-smokers. This method may be useful as a direct phenotyping approach to assess individual differences in uptake and metabolic activation of carcinogenic PAH.
benzo[a]pyrene metabolites; biomarker; metabolic activation; human urine
The asymmetric unit of the title compound, C32H38N2O5·2C2H6O, contains one main molecule and two solvent molecules, which interact via intermolecular O—H⋯O hydrogen bonds. The piperazine ring adopts a chair conformation. The crystal packing exhibits weak intermolecular C—H⋯O hydrogen bonds and voids of 31 Å3.
CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, β-catenin and vimentin) was examined in 144 gastric cancers by immunohistochemistry. Fifty-nine cases (41.0%) were defined as positive for CD146 expression. We found that CD146 expression correlated positively with lymph node involvement and a poor prognosis, and retained an independent prognostic factor for gastric cancer patients. Furthermore, positive expression of CD146 was strongly associated with loss of the epithelial marker E-cadherin and acquisition of the expression of the mesenchymal markers nuclear β-catenin and vimentin. These findings suggest that CD146 might promote EMT and progression in gastric cancer, and thus may be a potential therapeutic target for patients with gastric cancers.
CD146; gastric cancer; epithelial-mesenchymal transition; prognosis; immunohistochemistry
In the title molecule, C29H30Br2N2O3, the piperazine ring has a chair conformation and the C=C double bond has an E conformation. The dihedral angle between the bromobenzene rings is 79.1 (3)°. In the crystal, molecules are linked through C—H⋯O and C—H⋯Br hydrogen bonds.
The effect of endodontic involvement on tooth loss has not been quantified, so the present study aimed to assess this relationship after controlling for other relevant risk factors for tooth loss.
We analyzed data from 791 participants (18,798 teeth) in the Veterans Affairs Dental Longitudinal Study. Potential tooth- and person-level covariates were fitted into marginal proportional hazards models, including both apical radiolucencies (AR) and root canal therapy (RCT) status as time-dependent variables. Survival curves were plotted for teeth according to their AR and RCT status.
Both current AR and RCT status were associated with increased risk of tooth loss (p< 0.01), after controlling for baseline levels of periodontal disease, caries, tooth type, number of proximal contacts, number of teeth, age, education, and smoking history. Root canal filled (RCF) teeth seemed to have better survival than non-RCF teeth among teeth with AR, but worse survival than non-RCF teeth among teeth without AR.
Endodontic involvement was associated with tooth loss, controlling for other potential risk factors. Additional prospective studies are needed to provide better evidence as to the impact of endodontic involvement on tooth loss.
Apical radiolucency; endodontics; epidemiology; root canal therapy; survival analysis; tooth loss
In the title molecule, C26H23Br3N2O, the piperazine ring adopts a chair conformation and the C=C double bond has an E configuration. In the crystal, molecules are linked through weak intermolecular C—H⋯O hydrogen bonds.
In the title molecule, C28H28F2N2O2, the ethene bond exhibits an E conformation and the piperazine ring adopts a chair conformation. The amide-N atom of the piperazine ring is almost planar (bond-angle sum = 358.8°) whereas the other N atom is clearly pyramidal (bond-angle sum = 330.5°). The dihedral angle between the fluorobenzene rings is 76.36 (17)°. In the crystal, inversion dimers linked by pairs of C—H⋯O hydrogen bonds generate R
In the title molecule, C28H30N2O2, the piperazine ring adopts a chair conformation and the C=C bond exhibits an E conformation. The dihedral angle between the terminal phenyl rings is 71.4 (2). In the crystal, molecules are linked by C—H⋯O hydrogen bonds, forming  chains.