A novel tetracarboxylic dianhydride bearing a cycloaliphatic structure, (4arH,8acH)-decahydro-1t,4t:5c,8c-dimethanonaphthalene-2c,3c,6c,7c-tetracarboxylic 2,3:6,7-dianhydride (DNDA), was synthesized, and its structure was determined using X-ray crystallographic analysis. Polycondensation of DNDA or bicyclo[2.2.1]heptane-2-endo,3-endo,5-exo,6-exo-tetracarboxylic 2,3:5,6-dianhydride (BHDA) with a cycloaliphatic diamine, bis(aminomethyl)bicyclo[2.2.1]heptane (BBH) was carried out in HMPA. A viscous poly(amic acid) solution was obtained only when BBH was slowly added to the HMPA solution of the dianhydride, whereas the reverse adding order of the monomers resulted in precipitation due to salt formation. The poly(amic acid) solutions afforded nonaromatic polyimides as flexible and free-standing films after being cast and cured. The polyimide films were soluble in organic solvents such as DMAc and were colorless with a cutoff at wavelength shorter than 235 nm. The average refractive index of the BHDA−BBH polyimide film was 1.522, and the optical anisotropy, the difference between in-plane and out-of-plane indices, was nearly zero. The dielectric constant that was estimated from the refractive index according to the modified Maxwell equation was 2.55. The polyimides have good thermal stability with the 5% weight-loss temperatures around 450 °C. The polyimide films exhibit higher T g's over 290 °C. The high-temperature stability may be caused by the introduction of polyalicyclic structures, which results in an increase in the polymer main chain rigidity and less probability of main-chain scission.

Two tetracarboxylic dianhydrides with a polyalicyclic structure, bicyclo[2.2.2]octane-2-endo,3-endo,5-exo,6-exo-tetracarboxylic 2,3:5,6-dianhydride (5a) and bicyclo[2.2.2]octane-2-exo,3-exo,5-exo,6-exo-tetracarboxylic 2,3:5,6-dianhydride (5b), were synthesized, and polycondensations of the dianhydrides with aromatic diamines were carried out in well-purified N,N-dimethylacetamide (DMAc) at 85−105 °C under N2. The resulting poly(amic acid)s as precipitated possessed inherent viscosities in the range 0.5−0.1 dL/g. Some of the poly(amic acid)s formed flexible and tough films after curing. Polyimides were also obtained by a thermal solution imidization method where the DMAc solutions of poly(amic acid)s were heated at reflux temperature for 6 h. All of the examined polyimides were soluble at room temperature in aprotic and protic polar solvents such as DMAc and m-cresol. All of the polyimides showed excellent thermal stability with no significant weight loss up to approximately 400 °C, and the 5% weight loss temperatures in N2 were over 450 °C. The polyimides had glass transition temperatures over 380 °C except for the polyimides using 1,3-bis(4-aminophenoxy)benzene as an aromatic diamine. The flexible polyimide films possessed a tensile modulus range of 1.5−2.6 GPa, a tensile strength range of 52−96 MPa, an elongation at break of 3−11%, and a dielectric constant range of 3.2−3.7. These films exhibited cutoffs at wavelengths shorter than 320 nm and were entirely colorless. Normalized transparencies in the visible region (400−780 nm) were over 86% and, notably, the film prepared from 5a and 4,4‘-diaminodiphenyl ether had an excellent transparency of 94%. Colorlessness and transparency of the film at room temperature were maintained up to 200 °C when the film was heated in air and to 400 °C in N2. The polyimide of which the end group (the aromatic amino group) was capped using acetic anhydride was almost colorless even when heated at 300 °C in air.

These results suggest that determining F. nucleatum levels may help predict clinical outcomes in colorectal cancer patients. Further confirmatory studies using independent datasets are required to confirm our findings.

SUMMARY The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.

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BackgroundAdenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction in living cells. An isoform of this enzyme, adenylate kinase 4 (AK4), is localized in the mitochondrial matrix and is believed to be involved in stress, drug resistance, malignant transformation in cancer, and ATP regulation. However, the molecular basis for the AK4 functions remained to be determined.MethodsHeLa cells were transiently transfected with an AK4 small interfering RNA (siRNA), an AK4 short hairpin RNA (shRNA) plasmid, a control shRNA plasmid, an AK4 expression vector, and a control expression vector to examine the effect of the AK4 expression on cell proliferation, sensitivity to anti-cancer drug, metabolome, gene expression, and mitochondrial activity.ResultsAK4 knockdown cells treated with short hairpin RNA increased ATP production and showed greater sensitivity to hypoxia and anti-cancer drug, cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting AK4 knockdown cells into nude mice revealed that the grafted cells exhibited both slower proliferation and reduced the tumor sizes in response to CDDP. AK4 knockdown cell showed a increased oxygen consumption rate with FCCP treatment, while AK4 overexpression lowered it. Metabolome analysis showed the increased levels of the tricarboxylic acid cycle intermediates, fumarate and malate in AK4 knockdown cells, while AK4 overexpression lowered them. Electron microscopy detected the increased mitochondrial numbers in AK4 knockdown cells. Microarray analysis detected the increased gene expression of two key enzymes in TCA cycle, succinate dehydrogenase A (SDHA) and oxoglutarate dehydrogenease L (OGDHL), which are components of SDH complex and OGDH complex, supporting the metabolomic results.ConclusionsWe found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and the regulation of mitochondrial activity. These findings provide a new potential target for efficient anticancer therapies by controlling AK4 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0322-2) contains supplementary material, which is available to authorized users.

3:5, and its 1-methyl analogue (3b) were synthesized by a one-pot Diels-Alder (DA) reaction from maleic anhydride, and 4,5-dibromocyclohexane-l,2-dicarboxylic anhydride (2a) and 3-methyl-4,5-dibromocyclohexane-1,2dicarboxylic anhydride (2b), respectively. Each tetracarboxylic dianhydride was also prepared directly without isolation of the bromine adduct (2a or 2b) from the reaction product of bromine with 4-cyclohexene-l,2dicarboxylic anhydride (la) or 3-methyl-4-cyclohexene-1,2-dicarboxylic anhydride (lb). The polyimides prepared from 3a and 3b with aromatic diamines were soluble in aprotic and protic polar solvents and possessed molecular weights in the range from 1.6 x 104 to 4.6 X 104. The polyimide films were revealed to be almost colorless. Thermal gravimetric analysis gave an indication that these polyimides had good thermal stability with no significant weight loss up to approximately 360 °C. A thermal decomposition mechanism is proposed on the basis of GC-MS analysis on the pyrolyzed products of the model compounds 6a and 6b, and it is concluded that the decomposition in nitrogen was a consequence of the retro-DA reaction of polymer chains.

BackgroundIron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.MethodsThe effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.ResultsDFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.ConclusionsDFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.