Biomarkers and potential pathogenesis of colorectal cancer-related ischemic stroke.

AIM: To investigate the specific biomarkers and potential pathogenesis of colorectal cancer-related ischemic stroke (CRCIS). METHODS: A retrospective study was conducted on CRCIS patients (colorectal cancer patients with ischemic stroke without conventional stroke risk factors) registered at seven centers between January 2007 and December 2017. Clinical data and laboratory and imaging findings were compared with age- and sex- matched patients with colorectal cancer (CRC) without ischemic stroke that were admitted to the same hospital during the same period. Univariate and multivariate analyses were performed to analyze the independent risk factors for CRCIS. A receiver operator characteristic curve was configured to calculate the optimal cut-off value of the products of the independent risk factors for CRCIS. RESULTS: A total of 114 CRCIS patients and 114 CRC patients were included. Multiple lesions in multiple vascular territories were common in CRCIS patients (71, 62.28%). The levels of plasma D-dimer, carcinoembryonic antigen (CEA), cancer antigen 125, and neutrophil count were significantly higher in CRCIS patients than in CRC patients. Multiple logistic regression analysis revealed that plasma D-dimer levels [odds ratio (OR) = 1.002, 95% confidence interval (CI): 1.001-1.003, P < 0.001], CEA levels (OR = 1.011, 95%CI: 1.006-1.015, P < 0.001), and neutrophil count levels (OR = 1.626, 95%CI: 1.268-2.087, P < 0.001) were independent risk factors for CRCIS. In addition, receiver operator characteristic curve revealed that the area under curve for the products of plasma D-dimer, CEA, and neutrophil count was 0.889 ± 0.022 (95%CI: 0.847-0.932, P < 0.001), and the optimal cut-off value for the product was 252.06, which was called the CRCIS Index, with a sensitivity of 86.0% and specificity of 79.8%. CONCLUSION: Hypercoagulability induced by elevated CEA and neutrophils may be an important cause of CRCIS. The CRCIS index, which serves as a biomarker of CRCIS, needs further study.

Gastrointestinal toxicity induced by microcystins.

Microcystins (MCs) are produced by certain bloom-forming cyanobacteria that can induce toxicity in various organs, including renal toxicity, reproductive toxicity, cardiotoxicity, and immunosuppressive effects. It has been a significant global environmental issue due to its harm to the aquatic environment and human health. Numerous investigators have demonstrated that MC exposure can induce a widespread epidemic of enterogastritis with symptoms similar to food poisoning in areas close to lakes. Both in vivo and in vitro studies have provided evidence of positive associations between MC exposure and gastrointestinal toxicity. The toxicity of MCs on the gastrointestinal tract is multidimensional. MCs can affect gastrointestinal barrier function and shift the structure of gut microbiota in different gut regions. Furthermore, MCs can inhibit the secretion of gastrointestinal digestive enzymes and the release of inflammatory cytokines, which affects the expression of immune-related genes in the intestine. The damage of the intestine is closely correlated to MC exposure because the intestine is the main site for the digestion and absorption of nutrients. The damage to the gastrointestinal tract due to MCs was summarized from different aspects, which can be used as a foundation for further exploration of molecular damage mechanisms.

Endemic fluorosis in Henan province, China: ERα gene polymorphisms and reproductive hormones among women.

BACKGROUND AND OBJECTIVES: The aim of this study was to explore the influence of fluoride exposure and ERα gene polymorphisms on reproductive hormone concentrations of women in accordance with endemic fluorosis residence. METHODS AND STUDY DESIGN: A cross sectional study was conducted in Tongxu county, Henan Province, China. A total of 679 women were recruited using cluster sampling and each subject provided fasting blood and an associated urine sample. We measured the concentrations of serum gonadotropin releasing hormone (GnRH), follicle-stimulating hormone, luteinizing hormone, and estradiol and urinary fluoride. RESULTS: In the defluoridation project group (DFPG), serum GnRH was lower in women carrying C/C genotype compared to in those carrying C/T and T/T genotypes of ERα gene rs3798577 (p<0.05). In the endemic fluorosis group (EFG), serum GnRH was lower in women carrying Pp genotype compared to in those carrying PP and pp genotypes of ERα PvuII (p<0.05). Serum GnRH in women from EFG who carried Pp, pp, Xx and xx genotypes in ERα gene PvuII and XbaI was lower than in those in the control group (CG) who carried same genotypes (p<0.05). Furthermore, serum GnRH in women from EFG was significantly lower than in those in CG, regardless of whether the women were carrying C/C, C/T or T/T genotypes of ERα rs3798577 (p<0.05). Serum estradiol concentrations in EFG were significantly lower than in CG when the women were carrying the Pp, Xx and T/T genotypes in ERα gene (p<0.05). CONCLUSION: Interaction of ERα gene and fluoride exposure may influence women's serum reproductive hormone concentrations.

Effect of oxidative stress on fluoride-induced apoptosis in primary cultured Sertoli cells of rats.

This study examined the effect of oxidative stress on the apoptosis of Sertoli cells induced by sodium fluoride (NaF). Cell viability, reactive oxygen species, malondialdehyde content, superoxide dismutase activity, mitochondrial membrane potential, and apoptosis were measured after the rat Sertoli cells were exposed to various concentrations of (0, 6, 12, and 24 µg/ml) sodium fluoride in the presence and absence of 2 mM N-acetylcysteine (NAC) for 24 h. The present study showed that decrease in cell viability and excessive oxidative stress were observed in NaF-treated cells. The treatment with NAC restored the decreased cell viability and excessive oxidative stress. Moreover, fluoride exposure decreased mitochondrial membrane potential and increased apoptosis in Sertoli cells. NAC was also found to suppress a loss of mitochondrial membrane potential and the percentage of apoptosis in NaF-treated Sertoli cells. This study proved that oxidative stress probably play a major role in NaF-induced apoptosis of Sertoli cells.

[The influence of high fluoride exposure in drinking water on endocrine hormone in female].

OBJECTIVE: To explore the influence of water fluoride exposure on reproductive hormones in female. METHODS: Cross-sectional study was conducted in seven villages of a county in Henan province by using simple random sampling including high fluoride area, defluoridation project area and control area on April, 2011 based on the preliminary study results of fluoride concentration in drinking water. Women who were born and growth or lived in the village at least 5 years and aged 18-48 years old were recruited using cluster sampling. They were divided into high fluoride group (HFG, 116 subjects), defluoridation project group (DFPG, 132 subjects) and control group (CG, 227 subjects) in accordance with the above areas. All subjects accepted questionnaire and physical checkup. Fasting blood and morning urine samples were collected. The concentration of fluoride in urine was determined by fluoride ion selective electrode method. The serum level of GnRH was detected using enzyme linked immunosorbent assay (ELISA). The serum level of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) were determined by chemiluminesence immunoassay (CLIA). RESULTS: The average age was (39.44 ± 7.34), (38.84 ± 8.03), (37.45 ± 7.70) years old in female from DFPG, HFG and CG respectively, there were no significant differences among the three groups (F = 3.02, P = 0.05). The urine fluoride levels were (1.34 ± 1.07), (2.59 ± 1.57), (0.92 ± 0.46) mg/ml in female from DFPG, HFG and CG respectively, there was a significant difference among three groups (F = 105.38, P < 0.01). No significant differences were observed of serum GnRH, LH, T, FSH and E2 among three groups in follicular phase (P > 0.05). The serum levels of E2 in Ovulatory period were 67.73, 58.09, 84.96 pg/ml in female from DFPG, HFG and CG respectively. It was lower in HFG than that in CG (H = 4.00, P < 0.05). The serum levels of T in Ovulatory period were 0.55, 0.45, 0.55 ng/ml in female from DFPG, HFG and CG respectively. It was lower in HFG than that in DFPG (H = 6.47, P < 0.05), but no significant difference was observed between HFG and CG (H = 2.41, P > 0.05). The serum levels of GnRH in Luteal phase were 24.09, 20.16, 23.50 ng/ml in female from DFPG, HFG and CG respectively. It was lower in HFG than that in DFPG (H = 14.14, P < 0.05) and CG (H = 12.53, P < 0.05). The serum level of E2 in luteal phase were 81.47, 64.60, 74.55 pg/ml in female from DFPG, HFG and CG respectively. It was lower in HFG than that in DFPG (H = 5.69, P < 0.05). As for LH, FSH and T, no significant differences were observed among the three groups (P > 0.05 respectively). The abnormal rates of E2 level were 22.73 (30/102), 37.93 (44/72), 20.26 (46/181) in female from DFPG, HFG and CG respectively. The E2 abnormal rate in female from HFG was higher that from DFPG (χ(2) = 6.82, P < 0.05) and CG (χ(2) = 12.38, P < 0.05). CONCLUSION: Fluoride exposure may influence reproductive hormones in female, especially in ovulatory and luteal phase of menstrual cycle.

Sustained analgesia achieved through esterase-activated morphine prodrugs complexed with PAMAM dendrimer.

PURPOSE: Design and evaluate the in vitro and in vivo efficacy of two extended release morphine formulations developed for IV administration by complexing esterase activated morphine prodrugs to surface-modified, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer. METHODS: Prodrugs were synthesized, complexed with PAMAM dendrimer, characterized via ultra performance liquid chromatography (UPLC), nuclear magnatic resonance (NMR), and tested in vitro using rat plasma vs. saline control and in an in vivo rat and guinea pig pain model (modified Randall and Selitto test). RESULTS: We demonstrated that complexation with dendrimer allowed the solubilization of the prodrugs for in vivo applications without the need for salt, and that the structural design of the morphine prodrugs allowed the controlled release of morphine which extended the action of morphine-induced analgesia in an animal pain model from 2 h (control) to 6 h (Morphine Prodrug A). CONCLUSION: The concept of complexing/solubilizing appropriately designed esterase-sensitive prodrugs with dendrimer to enhance the sustained release of these drugs may be a useful pharmacokinetic strategy for a range of therapeutics.

ReaxFF molecular dynamics simulations of oxidation of toluene at high temperatures.

Aromatic hydrocarbon fuels, such as toluene, are important components in real jet fuels. In this work, reactive molecular dynamics (MD) simulations employing the ReaxFF reactive force field have been performed to study the high-temperature oxidation mechanisms of toluene at different temperatures and densities with equivalence ratios ranging from 0.5 to 2.0. From the ReaxFF MD simulations, we have found that the initiation consumption of toluene is mainly through three ways, (1) the hydrogen abstraction reactions by oxygen molecules or other small radicals to form the benzyl radical, (2) the cleavage of the C-H bond to form benzyl and hydrogen radicals, and (3) the cleavage of the C-C bond to form phenyl and methyl radicals. These basic reaction mechanisms are in good agreement with available chemical kinetic models. The temperatures and densities have composite effects on toluene oxidation; concerning the effect of the equivalence ratio, the oxidation reaction rate is found to decrease with the increasing of equivalence ratio. The analysis of the initiation reaction of toluene shows that the hydrogen abstraction reaction dominates the initial reaction stage at low equivalence ratio (0.5-1.0), while the contribution from the pyrolysis reaction increases significantly as the equivalence ratio increases to 2.0. The apparent activation energies, E(a), for combustion of toluene extracted from ReaxFF MD simulations are consistent with experimental results.

Influence of polluted SY River on child growth and sex hormones.

OBJECTIVE: To investigate the influence of the polluted SY River on children's growth and sex hormones, and provide scientific data for assessment of the polluted status of the SY River. METHODS: The study areas were selected randomly from the SY River Basin. Lead (Pb), mercury (Hg), arsenic (As), phthalates (DEP, DBP, DMP, DEHP), and bisphenol A (BPA) were measured both in the river water and in the drinking water. School children were selected by cluster sampling (n=154). Physical development indexes (height, weight, bust-circumference, and skinfold thickness) and sex hormones [testosterone (T) and estradiol (E2)] were measured for all the children. RESULTS: The contents of Pb and Hg exceeded Class V standards of surface water quality in each section of the river and other indicators exceeded Class III. Compared to the control area, the concentrations of Pb, Hg, As, BPA, DEP, and DBP in the drinking water were significantly higher than in the polluted area (P<0.05). Children from the control area had significantly lower E2 and T than children from the polluted area (P<0.05). Among anthropometric results, only skinfold thickness had statistically significant difference between the two groups (P<0.05), while the other indexes showed no significant differences between the two groups (P>0.05). CONCLUSION: The drinking water has been polluted by the SY River and affected serum sex hormone levels of children living in the polluted area.

Effects of fuel additives on the thermal cracking of n-decane from reactive molecular dynamics.

Thermal cracking of n-decane and n-decane in the presence of several fuel additives are studied in order to improve the rate of thermal cracking by using reactive molecular dynamics (MD) simulations employing the ReaxFF reactive force field. From MD simulations, we find the initiation mechanisms of pyrolysis of n-decane are mainly through two pathways: (1) the cleavage of a C-C bond to form smaller hydrocarbon radicals, and (2) the dehydrogenation reaction to form an H radical and the corresponding decyl radical. Another pathway is the H-abstraction reactions by small radicals including H, CH(3), and C(2)H(5). The basic reaction mechanisms are in good agreement with existing chemical kinetic models of thermal decomposition of n-decane. Quantum mechanical calculations of reaction enthalpies demonstrate that the H-abstraction channel is easier compared with the direct C-C or C-H bond-breaking in n-decane. The thermal cracking of n-decane with several additives is further investigated. ReaxFF MD simulations lead to reasonable Arrhenius parameters compared with experimental results based on first-order kinetic analysis. The different chemical structures of the fuel additives greatly affect the apparent activation energy and pre-exponential factors. The presence of diethyl ether (DEE), methyl tert-butyl ether (MTBE), 1-nitropropane (NP), 3,6,9-triethyl-3,6,9-trimethyl-1,2,4,5,7,8-hexaoxonane (TEMPO), triethylamine (TEA), and diacetonediperodixe (DADP) exhibit remarkable promoting effect on the thermal cracking rates, compared with that of pure n-decane, in the following order: NP > TEMPO > DADP > DEE (∼MTBE) > TEA, which coincides with experimental results. These results demonstrate that reactive MD simulations can be used to screen for fuel additives and provide useful information for more comprehensive chemical kinetic model studies at the molecular level.

Design, synthesis, and biological functionality of a dendrimer-based modular drug delivery platform.

A modular dendrimer-based drug delivery platform was designed to improve upon existing limitations in single dendrimer systems. Using this modular strategy, a biologically active platform containing receptor mediated targeting and fluorescence imaging modules was synthesized by coupling a folic acid (FA) conjugated dendrimer with a fluorescein isothiocyanate (FITC) conjugated dendrimer. The two different dendrimer modules were coupled via the 1,3-dipolar cycloaddition reaction ("click" chemistry) between an alkyne moiety on the surface of the first dendrimer and an azide moiety on the second dendrimer. Two simplified model systems were also synthesized to develop appropriate "click" reaction conditions and aid in spectroscopic assignments. Conjugates were characterized by (1)H NMR spectroscopy and NOESY. The FA-FITC modular platform was evaluated in vitro with a human epithelial cancer cell line (KB) and found to specifically target the overexpressed folic acid receptor.

Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

Spectral shift of the n → π* transition for acetone and formic acid with an explicit solvent model.

In our recent work, a new form of the electrostatic solvation energy for the nonequilibrium polarization has been derived by introducing the method of constrained equilibrium state in the framework of continuous medium theory. Up until now, the idea of the constrained equilibrium state method has not been introduced into the explicit solvent model by others; therefore this nonequilibrium energy form was further equivalently extended to the explicit solvent model in this work based on the discrete representation of the solvent permanent charges and induced dipoles. Making use of this expression in explicit solvent model, we modified the nonequilibrium module in the averaged solvent electrostatic potential/molecular dynamics program to implement numerical calculations. Subsequently, the new codes were applied to study the solvatochromic shifts of the n → π* absorption spectra for acetone and trans-formic acid in aqueous solution. The calculation results show a good agreement with the experimental observations. When our results of spectral shift are compared with those achieved directly from the continuum model, it can be seen that both the explicit solvent model and continuum model derived based on the constrained equilibrium approach can give reasonable predictions. The hydrogen bond effect was also discussed and deemed to be a dominant contribution to the spectral shift by calculating the n → π* absorption spectra of acetone-water complexes.

Plasma-mediated release of morphine from synthesized prodrugs.

Two morphine prodrugs ('PDA' and 'PDB') were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5-10min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse>rat>guinea pig>human). Morphine's release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK-NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios.

Serum calciotropic hormone levels, and dental fluorisis in children exposed to different concentrations of fluoride and iodine in drinking water.

BACKGROUND: High fluoride exposure can result in dental fluorosis. Fluoride and iodine are coexistent in the drinking water of areas in China and may affect the prevalence of dental fluorosis and osteogenesis. The aim of this study was to investigate the relationship between serum calciotropic hormone level, and dental fluorisis in children exposed to different concentrations of fluoride and iodine in drinking water. METHODS: A pilot study was conducted in three villages located in the Kaifeng and Tongxu counties of Henan Province, China in 2006. Children aged 8 to 12 years, born and raised in the three villages were recruited. The fluoride levels in the samples of urine from these children were detected by fluoride ion selective electrode. Calcitonin and osteocalcin levels in the serum, and serum calcium were measured by radioimmunassay and flame atomic absorption spectrometry, respectively. RESULTS: Fluoride levels in urine were significantly lower in children from control area (CA) as compared with those from the high fluoride & iodine areas (HFIA) and the high fluoride area (HFA) (P < 0.05 respectively), and no statistically significant difference was found between the children from HFIA and HFA. Additionally, calcitonin levels in the serum were significantly lower in children from CA and HFA as compared with that from HFIA (P < 0.05 respectively), and osteocalcin levels in the serum was lower in children from CA than those from HFIA (P < 0.05). No statistically significant difference in serum osteocalcin concentrations was found between children from HFA and HFIA. CONCLUSION: This study provides an evidence that iodine exposure may modify the serum calciotropic hormone levels related to fluorine exposure.

Vertical detachment energy of hydrated electron based on a modified form of solvent reorganization energy.

In this work, the constrained equilibrium principle is introduced and applied to the derivations of the nonequilibrium solvation free energy and solvent reorganization energy in the process of removing the hydrated electron. Within the framework of the continuum model, a modified expression of the vertical detachment energy (VDE) of a hydrated electron in water is formulated. Making use of the approximation of spherical cavity and point charge, the variation tendency of VDE accompanying the size increase of the water cluster has been inspected. Discussions comparing the present form of the VDE and the traditional one and the influence of the cavity radius in either the fixed pattern or the varying pattern on the VDE have been made.

[Study on the relationship between ER Rsa I gene polymorphism and children's dental fluorosis].

OBJECTIVE: To explore the distribution of ER Rsa I genotype in children who lived in the areas with or without high fluoride, and evaluate the relationship between ER Rsa I gene polymorphism and children's dental fluorosis. METHODS: Children aged 8 to 12 years, born and raised in high fluoride areas and control areas in two counties of Henan Province were recruited. The Rsa I marker of ER gene was genotyped in 237 children composed of both dental fluorosis cases and controls by PCR-RFLP procedure. Urine fluoride was detected with fluoride ion selective electrode method. RESULTS: The frequency distribution of ER Rsa I genotype was rr 60.81% (45/74), Rr 27.02% (20/74), RR 12.16% (9/74) in children with fluorosis; rr 73.91% (51/69), Rr 20.29% (14/69), RR 5.80% (4/69) in children without fluorosis from high fluoride areas, and rr 63.83% (60/94), Rr 34.04% (32/94), RR 2.13% (2/94) in the children without fluorosis from control areas respectively. There were no significant differences in the three groups (P>0.05), but children carrying allele R of ER Rsa I had a significantly increased risk of dental fluorosis (OR=1.821, 95% CI: 1.013-3.274) compared to children carrying the allele r in endemic fluorosis areas. CONCLUSION: Although no significant difference was found in ER Rsa I genotype between cases and non-dental fluorosis in endemic fluorosis areas, children carrying R allele of ER Rsa I had a higher risk compared to children carrying r allele, and the further study is needed.

Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs.

Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics.

The implications of stochastic synthesis for the conjugation of functional groups to nanoparticles.

Stochastic synthesis of a ligand coupled to a nanoparticle results in a distribution of populations with different numbers of ligands per nanoparticle. This distribution was resolved and quantified using HPLC and is in excellent agreement with the ligand/nanoparticle average measured by 1H NMR, gel permeation chromatography (GPC), and potentiometric titration, and yet significantly more disperse than commonly held perceptions of monodispersity. Two statistical models were employed to confirm that the observed heterogeneity is consistent with theoretical expectations.

Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors.

This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.