Preparation, characterization, and in vitro drug release behavior of biodegradable chitosan-graft-poly(1, 4-dioxan-2-one) copolymer

A novel copolymer of chitosan-g-poly(p-dioxanone) (CGP) was synthesized in bulk by ring-opening polymerization of p-dioxanone (PDO) initiated by the hydroxyl group or amino group of chitosan using SnOct₂ as catalyst. The chemical structure was determined by ¹H NMR. It was found that the feed ratio of chitosan to PDO had a great effect on the degree of polymerization (DP) and the substitution (DS) of PDO. The thermal stability and crystallization behavior of graft copolymer CGP were closely related to the values of DP and DS. When the resulting copolymer was used as Ibuprofen carrier, the release rate of Ibuprofen decreased compared with that of pure chitosan carrier. The drug release behavior was also influenced by the structure of graft copolymers.     

The antiapoptotic role of pregnane X receptor in human colon cancer cells

The orphan nuclear receptor pregnane X receptor (PXR) plays an important role in the detoxification of foreign and endogenous chemicals, including bile acids. PXR promotes bile acid elimination by activating bile acid-detoxifying enzymes and transporters. Certain bile acids are known to promote colonic carcinogenesis by inducing colon cancer cell apoptosis. However, whether and how PXR plays a role in colon cancer apoptosis has not been reported. In this study, we showed that activation of PXR by genetic (using a constitutively activated PXR) or pharmacological (using PXR agonist rifampicin) means protected the PXR-overexpressing colon cancer HCT116 cells from deoxycholic acid-induced apoptosis. Interestingly, activation of PXR also protected HCT116 cells from adriamycin-induced cell death, suggesting that the antiapoptotic effect of PXR was not bile acid specific. Moreover, the antiapoptotic effect of PXR in HCT116 cells appeared to be independent of xenobiotic enzyme regulation, because these cells had little basal and inducible expression of bile acid-detoxifying enzymes. Instead, SuperArray analysis showed that PXR-mediated deoxycholic acid resistance was associated with up-regulation of multiple antiapoptotic genes, including BAG3, BIRC2, and MCL-1, and down-regulation of proapoptotic genes, such as BAK1 and TP53/p53. Treatment with rifampicin in colon cancer LS180 cells, a cell line known to express endogenous PXR, also inhibited apoptosis. Activation of PXR in transgenic mice inhibited bile acid-induced colonic epithelial apoptosis and sensitized mice to dimethylhydrazine-induced colonic carcinogenesis, suggesting that the antiapoptotic effect of PXR is conserved in normal colon epithelium. In summary, our results have established the antiapoptotic role of PXR in both human colon cancer cells and normal mouse colon epithelium.     

Asymmetric synthesis of bicyclic piperidines via L-proline catalyzed aldol reaction of 3-phthalimidopropanal

A highly enantioselective approach for preparing optically active bicyclic piperidines is described. The key step for introducing chiral centers was a L-proline catalyzed direct enantioselective aldol reaction of 3-phthalimidopropanal with aliphatic ketones. In the reactions with alicyclic ketones, a highly enantioselective formation of anti-2-(3-phthalimido-1-hydroxypropyl)cycloketones 1a-1b (>99% ee) was observed. The aldol products 1 could be subsequently converted into bicyclic piperidines 2 via a consecutive reductive deprotection, acylation, ring closure, and hydrolysis.     

Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling

Toll-like receptors are involved in host defense against invading pathogens. The two members of this superfamily, IL-1R and TLR4, activate overlapping NF-kappaB activate signaling pathway mediated by TRAF6. In this study, we identified syntenin as a negative regulator of IL-1R and TLR4 mediated NF-kappaB activation. Overexpressed syntenin inhibited IL-1- or LPS-, but not TNF- induced NF-kappaB activation and IL-8 mRNA expression in a dose dependent manner. Syntenin specifically interacted with TRAF6 in human 293 cells, and inhibited TRAF6 induced NF-kappaB and AP-1 activation. Syntenin also associated with TRAF6 under physiological condition, and dissociated from TRAF6 upon IL-1 stimulation. This might be due to a competition between syntenin and IRAK1, as overexpression of IRAK1 disrupted the interaction of syntenin with TRAF6, and rescued syntenin induced reduction of TRAF6 ubiquitination. Moreover, knockdown of syntenin potentiated IL-1- or LPS- triggered NF-kappaB activation and IL-8 mRNA expression. These findings suggest that syntenin is a physiological suppressor of TRAF6 and plays an inhibitory role in IL-1R- and TLR4- mediated NF-kappaB activation pathways.     

Specialized host-plant performance of the cotton aphid is altered by experience

Although distinct host specialization is observed for the cotton-melon aphid (Aphis gossypii Glover) on cotton and cucurbit plants, it is still ambiguous whether the specialization is altered by experience on a novel host plant. Here the performance of cotton and cucurbit-specialized aphids, A. gossypii on novel host plants was studied by a host-selection test and by the life-table method. The two host-specialized aphids cannot survive and establish populations after reciprocal host transfers. They have ability to recognize the host plants on which they were reared, and escape behavior from novel hosts was observed. Interestingly, the cotton and cucurbit-specialized aphids survive and reproduce normally on hibiscus (Hibiscus syriacus), a main overwintering host plant, and host-fidelity of A. gossypii to cucurbit plants is altered by feeding and living experience on hibiscus, which confers the same capacity to use cotton and cucumber on to the cucurbit-specialized population, but host-fidelity to cotton is not altered and the fitness of the cotton specialized population to cucumber is still poorer. A. gossypii from hibiscus has a significant preference for cotton to cucumber in the host-selection process, and none stays on cucumber more than 20 h after transfer. The results presented imply that cucurbit-specialized aphids might not return to an overwintering host plant (hibiscus) in wild fields, so host conservatism to cucurbit plants is maintained. The potential of cucurbit-specialized aphids of A. gossypii to use cotton plants, intermediated by experience on hibiscus, suggests that the specialized host-plant performance of phytophagous insects is not wholly conservative.     

Photosystem 2 photochemistry and pigment composition of a yellow mutant of rice (<Emphasis Type="Italic">Oryza sativa</Emphasis> L.) under different irradiances

A yellow leaf colouration mutant (named ycm) generated from rice T-DNA insertion lines was identified with less grana lamellae and low thylakoid membrane protein contents. At weak irradiance [50 μmol(photon) m⁻² s⁻¹], chlorophyll (Chl) contents of ycm were ≈20 % of those of WT and Chl a/b ratios were 3-fold that of wild type (WT). The leaf of ycm showed lower values in the actual photosystem 2 (PS2) efficiency (Φ_PS2), photochemical quenching (q_P), and the efficiency of excitation capture by open PS2 centres 1 (F_v′/F_m′) than those of WT, except no difference in the maximal efficiency of PS2 photochemistry (F_v/F_m). With progress in irradiance [100 and 200 μmol(photon) m⁻² s⁻¹], there was a change in the photosynthetic pigment stoichiometry. In ycm, the increase of total Chl contents and the decrease in Chl a/b ratio were observed. Φ_PS2, q_P, and F_v′/F_m′ of ycm increased gradually along with the increase of irradiance but still much less than in WT. The increase of xanthophyll ratio [(Z+A)/(V+A+Z)] associated with non-photochemical quenching (q_N) was found in ycm which suggested that ycm dissipated excess energy through the turnover of xanthophylls. No significant differences in pigment composition were observed in WT under various irradiances, except Chl a/b ratio that gradually decreased. Hence the ycm mutant developed much more tardily than WT, which was caused by low photon energy utilization independent of irradiance.     

GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth

Here, we report the identification of GIDE, a mitochondrially located E3 ubiquitin ligase. GIDE contains a C-terminal RING finger domain, which is mostly conserved with those of the lAP family members and is required for GIDE＇s E3 ligase activity. Overexpression of GIDE induces apoptosis via a pathway involving activation of caspases, since caspase inhibitors, XIAP and an inactive mutant of caspase-9 block GIDE-induced apoptosis. GIDE also activates JNK, and blockage of JNK activation inhibits GIDE-induced release of cytochrome c and Smac as well as apoptosis, suggesting that JNK activation precedes release of cytochrome c and Smac and is required for GIDE- induced apoptosis. These pro-apoptotic properties of GIDE require its E3 ligase activity. When somewhat over-or underexpressed, GIDE slows or accelerates cell growth, respectively. These pro-apoptotic or growth inhibition effects of GIDE may account for its absence in tumor cells.     

Chronic mild stress impairs cognition in mice: from brain homeostasis to behavior

Exposure to chronic stress in rodents and psychosocial stress in humans has been shown to alter cognitive functions and has been linked to the pathophysiology of mood disorders. The purpose of the present study was to investigate effects and possible mechanisms of a chronic mild stress (CMS) procedure on cognitive behaviors in Swiss albino mice using the object recognition test (ORT) and object location test (OLT). Results showed that CMS exposure impaired cognitive performance and produced amnesia of acquired information in both ORT and OLT. Furthermore, the cognitive impairment was coexistent with increased plasma levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as with enhanced plasma levels of corticosterone (CORT), corticotrophin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH). In addition, severe neuronal cell damage was found, as bromodeoxyuridine (BrdU) positive cells and the expression of brain derived neurotrophic factor (BDNF) in dentate gyrus (DG) of hippocampus were decreased after 5 weeks CMS procedure. Taken together, these findings indicated that CMS exposure-induced impairment of cognitive behaviors might be attributed to the stress-related alterations in brain homeostasis that were reflected in changes in the neuroimmune and neuroendocrine systems as well as in neurogenesis.     

p190RhoGEF Binds to a destabilizing element in the 3' untranslated region of light neurofilament subunit mRNA and alters the stability of the transcript.

Stabilization of neurofilament (NF) mRNAs plays a major role in regulating levels of NF expression and in establishing axonal size and rate of axonal conduction. Previous studies have identified a 68-nucleotide destabilizing element at the junction of the coding region and 3' untranslated region of the light NF subunit (NF-L) mRNA. The present study has used the destabilizing element (probe A) to screen a rat brain cDNA library for interactive proteins. A cDNA clone encoding 1068 nucleotides in the C-terminal domain of p190RhoGEF (clone 39) was found to bind strongly and specifically to the RNA probe. The interaction was confirmed using a glutathione S-transferase/clone 39 fusion protein in Northwestern, gel-shift, and cross-linkage studies. The glutathione S-transferase/clone 39 fusion protein also enhanced the cross-linkage of a major 43-kDa protein in brain extract to the destabilizing element. Functional studies on stably transfected neuronal cells showed that p190RhoGEF expression increased the half-life of a wild-type NF-L mRNA but did not alter the half-life of a mutant NF-L mRNA lacking the destabilizing element. The findings reveal a novel interactive feature of p190RhoGEF that links the exchange factor with NF mRNA stability and regulation of the axonal cytoskeleton.