Glucose oxidation modulates anoikis and tumor metastasis

Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis or the Warburg effect, and the cells resist matrix detachment-induced apoptosis, which is called anoikis, a barrier to metastasis. It remains largely unclear whether tumor metabolism influences anoikis and metastasis. Here we show that when detached from the matrix, untransformed mammary epithelial cells undergo metabolic reprogramming by markedly upregulating pyruvate dehydrogenase (PDH) kinase 4 (PDK4) through estrogen-related receptor gamma (ERRγ), thereby inhibiting PDH and attenuating the flux of glycolytic carbon into mitochondrial oxidation. To decipher the significance of this metabolic response, we found that depletion of PDK4 or activation of PDH increased mitochondrial respiration and oxidative stress in suspended cells, resulting in heightened anoikis. Conversely, overexpression of PDKs prolonged survival of cells in suspension. Therefore, decreased glucose oxidation following cell detachment confers anoikis resistance. Unlike untransformed cells, most cancer cells demonstrate reduced glucose oxidation even under attached conditions, and thus they inherently possess a survival advantage when suspended. Normalization of glucose metabolism by stimulating PDH in cancer cells restores their susceptibility to anoikis and impairs their metastatic potential. These results suggest that the Warburg effect, more specifically, diminished glucose oxidation, promotes anoikis resistance and metastasis and that PDKs are potential targets for antimetastasis therapy.     

High temporal and individual variation in the prevalence and intensity of chytrid infection in the southernmost Leaf Frog of the genus Pithecopus (Anura,Phyllomedusidae)

Hydrobiologia - Pithecopus rusticus is an endemic amphibian restricted to the type locality, in southern Brazil, and possibly endangered to extinction, due to habitat degradation. However, an...     

Transcript-based redefinition of grouped oligonucleotide probe sets using AceView: High-resolution annotation for microarrays

Background  

Extracting biological information from high-density Affymetrix arrays is a multi-step process that begins with the accurate annotation of microarray probes. Shortfalls in the original Affymetrix probe annotation have been described; however, few studies have provided rigorous solutions for routine data analysis.     

An apoA-I mimetic peptibody generates HDL-like particles and increases alpha-1 HDL subfraction in mice

The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide. Like apoA-I, mFc-2X4F stabilized ABCA1 in J774A.1 and THP1 cells. The peptibody formed larger HDL particles when incubated with cultured cells compared with those by apoA-I. Interestingly, when administered to mice, mFc-2X4F increased both pre-β and α-1 HDL subfractions. The lipid-bound mFc-2X4F was mostly in the α-1 migrating subfraction. Most importantly, mFc-2X4F and apoA-I were found to coexist in the same HDL particles formed in vivo. These data suggest that the apoA-I mimetic peptibody is capable of mimicking apoA-I to generate HDL particles. The peptibody and apoA-I may work cooperatively to generate larger HDL particles in vivo, either at the cholesterol efflux stage and/or via fusion of HDL particles that were generated by the peptibody and apoA-I individually.     

Structural basis of electron transfer modulation in the purple CuA center

The X-ray structure of an engineered purple CuA center in azurin from Pseudomonas aeruginosa has been determined and refined at 1.65 A resolution. Two independent purple CuA azurin molecules are in the asymmetric unit of a new P21 crystal, and they have nearly identical conformations (rmsd of 0.27 A for backbone atoms). The purple CuA azurin was produced by the loop-engineering strategy, and the resulting overall structure is unperturbed. The insertion of a slightly larger Cu-binding loop into azurin causes the two structural domains of azurin to move away from each other. The high-resolution structure reveals the detailed environment of the delocalized mixed-valence [Cu(1.5).Cu(1.5)] binuclear purple CuA center, which serves as a useful reference model for other native proteins, and provides a firm basis for understanding results from spectroscopic and functional studies of this class of copper center in biology. The two independent Cu-Cu distances of 2.42 and 2.35 A (with respective concomitant adjustments of ligand-Cu distances) are consistent with that (2.39 A) obtained from X-ray absorption spectroscopy with the same molecule, and are among the shortest Cu-Cu bonds observed to date in proteins or inorganic complexes. A comparison of the purple CuA azurin structure with those of other CuA centers reveals an important relationship between the angular position of the two His imidazole rings with respect to the Cu2S2(Cys) core plane and the distance between the Cu and the axial ligand. This relationship strongly suggests that the fine structural variation of different CuA centers can be correlated with the angular positions of the two histidine rings because, from these positions, one can predict the relative axial ligand interactions, which are responsible for modulating the Cu-Cu distance and the electron transfer properties of the CuA centers.     

不同生态环境对蒲公英超氧物歧化酶（SOD）的影响

选择干生,湿生,阳生,阴生四种生境中生长的蒲公英Taraxacum mongolicum Hand.-Mazz分根,叶,花分别测定了SOD活性和比活性,并比较了同工酶谱的变化情况,结果表明不同生境未能改变SOD的同工酶条带数,但对其活性大小有影响,这种影响尤其表现在根上,湿生和阴生根的SOD活性明显高于干生和阳生根的SOD活性,显示出蒲公英的不同器官适应不同的环境效应。     

Pyrethroids as Promising Marine Antifoulants: Laboratory and Field Studies

Due to the regulations and bans regarding the use of traditional toxic chemicals against marine fouling organisms and the practical impediments to the commercialization of natural product antifoulants, there is an urgent need for compounds that are antifouling-active, environmentally friendly, and have a potential for commercial application. In this study, a series of common, commercially available pyrethroid products, which are generally used as environmentally safe insecticides, was evaluated for antifouling activity in the laboratory using an anti-settlement test with cyprids of the barnacle Balanus albicostatus and also in a field experiment. Laboratory assay showed that all eleven pyrethroids (namely, rich d-trans-allethrin, Es-biothrin, rich d-prallethrin, S-prallethrin, tetramethrin, rich d-tetramethrin, phenothrin, cyphenothrin, permethrin, cypermethrin, and high active cypermethrin) were able to inhibit barnacle settlement (EC₅₀ range of 0.0316 to 87.00 μg/ml) without significant toxicity. Analysis of structure–activity relationships suggested that the cyano group at the α-carbon position had a significant influence on the expression of antifouling activity in pyrethroids. In the field, the antifouling activity of pyrethroids was further confirmed, with the most potent pyrethroids being cypermethrin and high active cypermethrin, which displayed efficiency comparable with that of tributyltin. In summary, our investigation indicated that these pyrethroids have a great and practical commercial potential as antifouling agents.     

Effect of interleukin-10 on the Paracoccidioides brasiliensis killing by gamma-interferon activated human neutrophils

Paracoccidioidomycosis, a deep mycosis endemic in Latin America, is a chronic granulomatous disease caused by the fungus Paracoccidioides brasiliensis. Phagocytic cells play a critical role against this fungus, and several studies have shown the effects of activator and suppressive cytokines on macrophage and monocyte functions. However, studies on polymorphonuclear neutrophils (PMNs), that are the first cells recruited to the infection sites, are scarcer. Thus, the objective of this paper was to assess whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to block the activity of IFN-gamma-activated human PMNs upon P. brasiliensis intracellular killing, in vitro. The results showed that IFN-gamma-activated PMNs have an effective fungicidal activity against the fungus. This activity was associated with the release of high levels of H(2)O(2), the metabolite involved in phagocytic cells antifungal activities. However, the concomitant incubation of these cells with IFN-gamma and IL-10 significantly blocked IFN-gamma activation. As a consequence, PMNs killing activity and H(2)O(2) release were inhibited. Together, our results show the importance of PMNs exposure to activator or suppressor cytokines in the early stages of paracoccidioidomycosis infection.     

酒精摄入量对小鼠肠道微生物、酶活性和血常规的影响

【背景】酒是影响机体健康的一把"双刃剑",饮酒对机体肠道微生态体系具有重要影响。【目的】研究不同酒精摄入量对小鼠肠道微生物、酶活性及血常规的影响,从肠道微生态和血常规角度探讨饮酒对身体健康的影响及作用机制。【方法】将SPF(Specific pathogen free)级实验小鼠随机分为对照组、低酒精量摄入组、中酒精量摄入组和高酒精量摄入组。对照组给予蒸馏水饮用,其余各组分别给予10%、20%和30%(体积比)的酒精水溶液作为小鼠的唯一饮用水,连续1个月后采集回肠内容物进行微生物和酶活性分析,采集眼球血进行血常规分析。【结果】与对照组相比,低酒精量摄入组小鼠肠道内乳酸菌数量显著增加(P0.05),大肠杆菌和细菌总数显著降低(P0.01或P0.05);高酒精量摄入组小鼠肠道乳酸菌、双歧杆菌数量显著降低(P0.01);与低酒精量摄入组和中酒精量摄入组相比,高酒精量摄入组小鼠肠道木聚糖酶、纤维素酶、蛋白酶和淀粉酶活性显著升高(P0.01);与对照组相比,低酒精量摄入组小鼠的红细胞比容显著降低(P0.05)。【结论】高酒精摄入量小鼠肠道有益菌群数量相对减少,肠道屏障功能受到影响;低酒精摄入量能调节小鼠肠道菌群结构和消化酶相对活性。     

The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair

Nucleotide excision repair (NER) is the only mechanism in humans to repair UV-induced DNA lesions such as pyrimidine (6-4) pyrimidone photoproducts and cyclobutane pyrimidine dimers (CPDs). In response to UV damage, the ataxia telangiectasia mutated and Rad3-related (ATR) kinase phosphorylates and activates several downstream effector proteins, such as p53 and XPA, to arrest cell cycle progression, stimulate DNA repair, or initiate apoptosis. However, following the completion of DNA repair, there must be active mechanisms that restore the cell to a prestressed homeostatic state. An important part of this recovery must include a process to reduce p53 and NER activity as well as to remove repair protein complexes from the DNA damage sites. Since activation of the damage response occurs in part through phosphorylation, phosphatases are obvious candidates as homeostatic regulators of the DNA damage and repair responses. Therefore, we investigated whether the serine/threonine wild-type p53-induced phosphatase 1 (WIP1/PPM1D) might regulate NER. WIP1 overexpression inhibits the kinetics of NER and CPD repair, whereas WIP1 depletion enhances NER kinetics and CPD repair. This NER suppression is dependent on WIP1 phosphatase activity, as phosphatase-dead WIP1 mutants failed to inhibit NER. Moreover, WIP1 suppresses the kinetics of UV-induced damage repair largely through effects on NER, as XPD-deficient cells are not further suppressed in repairing UV damage by overexpressed WIP1. Wip1 null mice quickly repair their CPD and undergo less UV-induced apoptosis than their wild-type counterparts. In vitro phosphatase assays identify XPA and XPC as two potential WIP1 targets in the NER pathway. Thus WIP1 may suppress NER kinetics by dephosphorylating and inactivating XPA and XPC and other NER proteins and regulators after UV-induced DNA damage is repaired.