MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma

MicroRNAs (miRNAs) are dysregulated in many types of malignancies, including human hepatocellular carcinoma (HCC). MiR-107 has been implicated in several types of cancer regulation; however, relatively little is known about miR-107 in human HCC. In the present study, we showed that the overexpression of miR-107 accelerates the tumor progression of HCC in vitro and in vivo through its new target gene, CPEB3. Furthermore, our results demonstrated that CPEB3 is a newly discovered tumor suppressor that acts via the EGFR pathway. Therefore, our study demonstrates that the newly discovered miR-107/CPEB3/EGFR axis plays an important role in HCC progression and might represent a new potential therapeutic target for HCC treatment.     

Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer

Background

Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.

Methods

Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients'' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.

Results

Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.

Conclusions

This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.     

Serum 25-hydroxyvitamin D and bone mineral density in a racially and ethnically diverse group of men

CONTEXT: Although racial and ethnic differences in vitamin D status and bone mineral density (BMD) are recognized, less is known about how differences in vitamin D status impact BMD, especially among men. OBJECTIVE: Our objective was to examine the relation between serum 25-hydroxyvitamin D [25(OH)D] and BMD by race and ethnic group. DESIGN: We conducted a population-based, observational survey. Participants: Participants included 1114 Black, Hispanic, and White men, 30-79 yr of age. Outcomes: We assessed 25(OH)D by a competitive protein binding assay and BMD by dual-energy x-ray absorptiometry. RESULTS: Mean age +/- SD of the 331 Black, 362 Hispanic, and 421 White men was 48 +/- 12.8 yr. Mean 25(OH)D was lower among Black (25.0 +/- 14.7 ng/ml) and Hispanic (32.9 +/- 13.9 ng/ml) men compared with White men (37.4 +/- 14.0 ng/ml, P < 0.01). A higher percentage of both Black (44%) and Hispanic (23%) men had levels of 25(OH)D in the lowest quartile, compared with 11% of White men (P < 0.001). After adjusting for age, height, and weight, only White men showed significant positive correlation between 25(OH)D and BMD (range of correlations, 0.00-0.14). Serum 25(OH)D was not associated with BMD in Black or Hispanic men at any bone site. Results were similar when adjusted for age only. CONCLUSIONS: Our findings confirm substantial racial and ethnic group differences in BMD and serum 25(OH)D in men. Serum 25(OH)D and BMD are significantly related to one another in White men only. This may have implications for evaluation of bone health and supplementation in men with low levels of 25(OH)D. Further understanding of the biological mechanisms for these differences between race and ethnic groups is needed.     

Applications of supercritical CO2 in the fabrication of polymer systems for drug delivery and tissue engineering

Supercritical CO(2) has the potential to be an excellent environment within which controlled release polymers and dry composites may be formed. The low temperature and dry conditions within the fluid offer obvious advantages in the processing of water, solvent or heat labile molecules. The low viscosity and high diffusivity of scCO(2) offer the possibility of novel processing routes for polymer drug composites, but there are still technical challenges to overcome. Moreover, the low solubility of most drug molecules in scCO(2) presents both challenges and advantages. This review explores the current methods that use high pressure and scCO(2) for the production of drug delivery systems and the more specialized application of the fluid in the formation of highly porous tissue engineering scaffolds.     

Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.     

Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor

Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4-(trifluoromethyl)benzamide ( 18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1 IC 50 = 0.80 +/- 0.05 microM, COX-2 IC 50 = 210 +/- 10 microM). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.     

Propofol pretreatment attenuates LPS-induced granulocyte-macrophage colony-stimulating factor production in cultured hepatocytes by suppressing MAPK/ERK activity and NF-kappaB translocation

Propofol (PPF), a widely used intravenous anesthetic for induction and maintenance of anesthesia during surgeries, was found to possess suppressive effect on host immunity. This study aimed at investigating whether PPF plays a modulatory role in the lipopolysaccharide (LPS)-induced inflammatory cytokine expression in a cell line of rat hepatocytes. Morphological observation and viability assay showed that PPF exhibits no cytotoxicity at concentrations up to 300 microM after 48 h incubation. Pretreatment with 100 microM PPF for 24 h prior to LPS stimulation was performed to investigate the modulatory effect on LPS-induced inflammatory gene production. The results of semi-quantitative RT-PCR demonstrated that PPF pretreatment significantly suppressed the LPS-induced toll-like receptor (TLR)-4, CD14, tumor necrosis factor (TNF)-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression. Western blotting analysis showed that PPF pretreatment potentiated the LPS-induced TLR-4 downregulation. Flow cytometrical analysis revealed that PPF pretreatment showed no modulatory effect on the LPS-upregulated CD14 expression on hepatocytes. In addition, PPF pretreatment attenuated the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and IkappaBalpha, as well as the nuclear translocation of NF-kappaB primed by LPS. Moreover, addition of PD98059, a MAPK kinase inhibitor, significantly suppressed the LPS-induced NF-kappaB nuclear translocation and GM-CSF production, suggesting that the PPF-attenuated GM-CSF production in hepatocytes may be attributed to its suppressive effect on MAPK/ERK signaling pathway. In conclusion, PPF as an anesthetic may clinically benefit those patients who are vulnerable to sepsis by alleviating sepsis-related inflammatory response in livers.