Combination of capecitabine and ludartin inhibits colon cancer growth in mice

Purpose: To investigate the efficacy of capecitabine and ludartin in the treatment of colon cancer in mice.Methods: Mice model of colon cancer was used in this study. Quantitative real-time polymerase chain reaction (Qrt-PCR) was used to quantify the expression of vascular endothelial growth factor (VEGF) mRNA. Micro-vessel density was assessed using immunohistochemical analysis.Results: When administered separately, capecitabine and ludartin treatments significantly suppressed tumor growth in the mice model of colon cancer for 4 weeks, compared to control group. Coadministration of capecitabine and ludartin significantly inhibited tumor growth for 6 weeks (p < 0.05). Symptoms of colon cancer such as weight loss, skin discoloration and leukopenia were observed in untreated control group. However, these symptoms were completely absent in the group treated with combination of capecitabine and ludartin. The combined treatment also prevented colon cancer-induced increase in white blood cell (WBC) count, and increased median survival time of colon cancer mice from 38 to 55 days. Expression of VEGF in combination (capecitabine + ludartin) treatment group was significantly lower than in the control, i.e., untreated group (p ˂ 0.05). The combination treatment group also had significantly lower micro-vessel density in the tumor tissues, compared to the  ntreated control mice (p < 0.05).Conclusion: These results show that a combination treatment of capecitabine and ludartin effectively inhibits colon tumor growth and angiogenesis in mice via a mechanism involving suppression of VEGF expression. Thus, capecitabine and ludartin combination is a potentially  uitable treatment for colon cancer.Keywords: Colon cancer, Mice, Ludartin, Leukopenia, VEGF expression, Angiogenesi

Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation

Chronic wounds and the accompanying inflammation are ongoing challenges in clinical treatment. They are usually accompanied by low pH and high oxidative stress environments, limiting cell growth and proliferation. Ordinary medical gauze has limited therapeutic effects on chronic wounds, and there is active research to develop new wound dressings. The chitosan hydrogel could be widely used in biomedical science with great biocompatibility, but the low mechanical properties limit its development. This work uses polyacrylamide to prepare double-network (DN) hydrogels based on bioadhesive catechol-chitosan hydrogels. Cystamine and N, N′-Bis(acryloyl)cystamine, which can be cross-linking agents with disulfide bonds to prepare redox-responsive DN hydrogels and pH-responsive nanoparticles (NPs) prepared by acetalized cyclodextrin (ACD) are used to intelligently release drugs against chronic inflammation microenvironments. The addition of catechol groups and ACD-NPs loaded with the Resolvin E1 (RvE1), promotes cell adhesion and regulates the inflammatory response at the wound site. The preparation of the DN hydrogel in this study can be used to treat and regulate the inflammatory microenvironment of chronic wounds accurately. It provides new ideas for using inflammation resolving factor loaded in DN hydrogel of good biocompatibility with enhanced mechanical properties to intelligent regulate the wound inflammation and promote the wound repaired

Effects of condensed tannins from Leucaena on methane reduction, rumen fermentation and populations of methaogens and protozoa in vitro

Different levels of purified condensed tannins (CT) extracted from Leucaena leucocephala hybrid-Rendang (LLR) were investigated for their effects on CH4 production, rumen fermentation parameters such as pH, dry matter (DM) degradability, N disappearance and volatile fatty acid (VFA) concentrations, as well as on populations of rumen methanogenic archaea and protozoa in vitro. Purified CT concentrations of 0 (control), 10, 15, 20, 25 and 30 mg, and 500 mg of oven dried guinea grass (Panicum maximum) with 40 ml of buffered rumen fluid were incubated for 24 h using an in vitro gas production procedure. Total gas (ml/g DM) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.05) with increased levels of CT inclusion. CH4 production (ml/g DM) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.01) with increasing levels of CT. Total VFA concentration (mmol/L) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.01) with increasing CT inclusions. In vitro DM degradation and N disappearance declined linearly (P < 0.01) with increasing levels of CT. Estimates of rumen methanogenic archaea and protozoa populations using microbiological methods and real-time PCR assay showed linear reductions in total methanogens (P < 0.01) and total protozoa (P < 0.01) with increasing levels of CT. Methanogens in the order Methanobacteriales also declined, but with quadratic and cubic aspects. Results suggest that CT from LLR at a relatively low level of 15 mg of CT/500 mg DM reduce CH4 production by 47%, with only 7% reduction in degradation of feed DM. However, higher CT inclusions, while further reducing CH4 emissions, have substantive negative effects on DM digestibility

Intelligent H2S release coating for regulating vascular remodeling

Coronary atherosclerotic lesions exhibit a low-pH chronic inflammatory response. Due to insufficient drug release control, drug-eluting stent intervention can lead to delayed endothelialization, advanced thrombosis, and unprecise treatment. In this study, hyaluronic acid and chitosan were used to prepare pH-responsive self-assembling films. The hydrogen sulfide (H2S) releasing aspirin derivative ACS14 was used as drug in the film. The film regulates the release of the drug adjusted to the microenvironment of the lesion, and the drug balances the vascular function by releasing the regulating gas H2S, which comparably to NO promotes the self-healing capacity of blood vessels. Drug releasing profiles of the films at different pH, and other biological effects on blood vessels were evaluated through blood compatibility, cellular, and implantation experiments. This novel method of self-assembled films which H2S in an amount, which is adjusted to the condition of the lesion provides a new concept for the treatment of cardiovascular diseases

Comprehensive identification of alternative back-splicing in human tissue transcriptomes

Circular RNAs (circRNAs) are covalently closed RNAs derived from back-splicing of genes across eukaryotes. Through alternative back-splicing (ABS), a single gene produces multiple circRNAs sharing the same back-splice site. Although many ABS events have recently been discovered, to what extent ABS involves in circRNA biogenesis and how it is regulated in different human tissues still remain elusive. Here, we reported an in-depth analysis of ABS events in 90 human tissue transcriptomes. We observed that ABS occurred for about 84% circRNAs. Interestingly, alternative 5\u27 back-splicing occurs more prevalently than alternative 3\u27 back-splicing, and both of them are tissue-specific, especially enriched in brain tissues. In addition, the patterns of ABS events in different brain regions are similar to each other and are more complex than the patterns in non-brain tissues. Finally, the intron length and abundance of Alu elements positively correlated with ABS event complexity, and the predominant circRNAs had longer flanking introns and more Alu elements than other circRNAs in the same ABS event. Together, our results represent a resource for circRNA research-we expanded the repertoire of ABS events of circRNAs in human tissue transcriptomes and provided insights into the complexity of circRNA biogenesis, expression, and regulation

Hydrothermal synthesis and crystal structure of Na2In2[PO3(OH)]4·H2O with a new structure type

A sodium indium hydrogen phosphate hydrate, Na2In2[PO3 (OH)](4).H2O, was synthesized under mild hydrothermal conditions, and the crystal structure was characterized by the single-crystal X-ray diffraction method. The structure is of a new type with the following data: Mr = 794.775, triclinic, aP62, P-1 (No. 2), a = 9.3013(1) Angstrom, b = 9.4976(1) Angstrom, c = 9.2685(7) Angstrom, alpha = 98.710(4)degrees, beta = 98.953(4)degrees gamma = 60.228(6)degrees V = 699.42(5) Angstrom (3), Z = 2, D-x = 3.217 g cm(-3), lambda = 0.71073 Angstrom, mu = 39.1 cm(-1), F(000) = 644, T = 293 K, R = 0.0551, wR = 0.1528 for 245 variables and 4559 contributing unique reflections. The structure is characterized by corner-sharing InO6 and PO4H polyhedra forming a three-dimensional network with infinite channels along the [100] direction, where sodium cations and water molecules reside through hydrogen bonds. The topological construction of the title structure can be considered closely related to an augmented corundum network and the augmentation of the 4, 6 net has largely increased the porosity of the compound. The thermal stability investigation shows that the compound loses its water molecules around 365 degreesC and is nonzeolitic in character. (C) 2001 Academic Press

DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylation in response to DNA damage and cell cycle progression

<p>Abstract</p> <p>Background</p> <p>When DNA double-strand breaks (DSB) are induced by ionizing radiation (IR) in cells, histone H2AX is quickly phosphorylated into γ-H2AX (p-S139) around the DSB site. The necessity of DNA-PKcs in regulating the phosphorylation of H2AX in response to DNA damage and cell cycle progression was investigated.</p> <p>Results</p> <p>The level of γH2AX in HeLa cells increased rapidly with a peak level at 0.25 - 1.0 h after 4 Gy γ irradiation. SiRNA-mediated depression of DNA-PKcs resulted in a strikingly decreased level of γH2AX. An increased γH2AX was also induced in the ATM deficient cell line AT5BIVA at 0.5 - 1.0 h after 4 Gy γ rays, and this IR-increased γH2AX in ATM deficient cells was dramatically abolished by the PIKK inhibitor wortmannin and the DNA-PKcs specific inhibitor NU7026. A high level of constitutive expression of γH2AX was observed in another ATM deficient cell line ATS4. The alteration of γH2AX level associated with cell cycle progression was also observed. HeLa cells with siRNA-depressed DNA-PKcs (HeLa-H1) or normal level DNA-PKcs (HeLa-NC) were synchronized at the G1 phase with the thymidine double-blocking method. At ~5 h after the synchronized cells were released from the G1 block, the S phase cells were dominant (80%) for both HeLa-H1 and HeLa-NC cells. At 8 - 9 h after the synchronized cells released from the G1 block, the proportion of G2/M population reached 56 - 60% for HeLa-NC cells, which was higher than that for HeLa H1 cells (33 - 40%). Consistently, the proportion of S phase for HeLa-NC cells decreased to ~15%; while a higher level (26 - 33%) was still maintained for the DNA-PKcs depleted HeLa-H1 cells during this period. In HeLa-NC cells, the γH2AX level increased gradually as the cells were released from the G1 block and entered the G2/M phase. However, this γH2AX alteration associated with cell cycle progressing was remarkably suppressed in the DNA-PKcs depleted HeLa-H1 cells, while wortmannin and NU7026 could also suppress this cell cycle related phosphorylation of H2AX. Furthermore, inhibition of GSK3β activity with LiCl or specific siRNA could up-regulate the γH2AX level and prolong the time of increased γH2AX to 10 h or more after 4 Gy. GSK3β is a negative regulation target of DNA-PKcs/Akt signaling via phosphorylation on Ser9, which leads to its inactivation. Depression of DNA-PKcs in HeLa cells leads to a decreased phosphorylation of Akt on Ser473 and its target GSK3β on Ser9, which, in other words, results in an increased activation of GSK3β. In addition, inhibition of PDK (another up-stream regulator of Akt/GSK3β) by siRNA can also decrease the induction of γH2AX in response to both DNA damage and cell cycle progression.</p> <p>Conclusion</p> <p>DNA-PKcs plays a dominant role in regulating the phosphorylation of H2AX in response to both DNA damage and cell cycle progression. It can directly phosphorylate H2AX independent of ATM and indirectly modulate the phosphorylation level of γH2AX via the Akt/GSK3 β signal pathway.</p