Steroids in the treatment of IgA nephropathy to the improvement of renal survival: a systematic review and meta-analysis

Background

Studies have shown that steroids can improve kidney survival and decrease the risk of proteinuria in patients with Immunoglobulin A nephropathy, but the overall benefit of steroids in the treatment of Immunoglobulin A nephropathy remains controversial. The aim of this study was to evaluate the benefits and risks of steroids for renal survival in adults with Immunoglobulin A nephropathy.

Methodology and Principal Findings

We searched the Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE and EMBASE databases. All eligible studies were measuring at least one of the following outcomes: end-stage renal failure, doubling of serum creatinine and urinary protein excretion. Fifteen relevant trials (n = 1542) that met our inclusion criteria were identified. In a pooled analysis, steroid therapy was associated with statistically significant reduction of the risk in end-stage renal failure (RR: 0.46, 95% CI: 0.27 to 0.79), doubling of serum creatinine (RR = 0.34, 95%CI = 0.15 to 0.77) and reduced urinary protein excretion (MD = −0.47g/day, 95%CI = −0.64 to −0.31).

Conclusions/Significance

We identified that steroid therapy was associated with a decrease of proteinuria and with a statistically significant reduction of the risk in end-stage renal failure. Moreover, subgroup analysis also suggested that long-term steroid therapy had a higher efficiency than standard and short term therapy.     

TSA1 interacts with CSN1/CSN and may be functionally involved in Arabidopsis seedling development in darkness

The COP9 signalosome (CSN) is a multiprotein complex which participates in diverse cellular and developmental processes.CSN1,one of the subunits of CSN,is essential for assembly of the multiprotein complex via PCI (proteasome,COP9 signalosome and initiation factor 3) domain in the C-terminal half of CSN 1.However,the role of the N-terminal domain (NTD) of CSN 1,which is critical for the function of CSN,is not completely understood.Using a yeast two-hybrid (Y2H) screen,we found that the NTD of CSN1 interacts with TSK-associating protein 1 (TSA1),a reported Ca2+-binding protein.The interaction between CSN1 and TSA1 was confirmed by co-immunoprecipitation in Arabidopsis.tsal mutants exhibited a short hypocotyl phenotype in darkness but were similar to wild-type Arabidopsis under white light,which suggested that TSA1 might regulate Arabidopsis hypocotyl development in the dark.Furthermore,the expression of TSA1 was significantly lower in a csnl null mutant (fus6),while CSN1 expression did not change in a tsal mutant with weak TSA1 expression.Together,these findings suggest a functional relationship between TSA1 and CSN1 in seedling development.     

Determination of energy and amino acid digestibility in growing pigs fed corn distillers' dried grains with solubles containing different lipid levels

Two experiments were conducted to estimate the digestibility of energy, nitrogen and amino acids (AA) in growing pigs fed diets containing one of five corn distillers' dried grains with solubles (DDGS), including three normal oil DDGS (NO-DDGS) and two low oil DDGS (LO-DDGS) samples. Exp. 1 was conducted to determine the digestible energy (DE) and metabolisable energy (ME) content. Six growing barrows (initial body weight [BW]: 35.1 +/- 2.2 kg) were allotted to a 6 x 6 Latin square design, with six periods and six diets. One diet was a corn soybean meal basal diet and the other five diets were based on corn, soybean meal and 28.8% DDGS. The average DE and ME values for the three NO-DDGS samples were 16.0 and 14.9 MJ/kg dry matter (DM). These values were 9 and 13% greater than the LO-DDGS values of 14.7 and 13.2 MJ/kg DM respectively. Exp. 2 was conducted to determine and compare apparent (AID) and standardised (SID) ileal digestibility for crude protein and AA in the five DDGS samples. Six growing barrows (initial BW, 32.2 +/- 1.9 kg) fitted with a simple T-cannula were allotted to a 6 x 6 Latin square design with six periods and six diets. Five of the diets were based on the five DDGS samples, and the remaining one diet was nitrogen-free diet based on cornstarch and sucrose. Titanium dioxide (0.1%) was used as inert marker. The results of the experiment showed the largest variation among the different samples in AID and SID for lysine (from 41.8 to 65.8% and 53.8 to 73.9% respectively) and threonine (from 54.3 to 73.8% and 65.2 to 79.5% respectively). Also, among the indispensable AA, the SID values for arginine, histidine, threonine and tryptophan observed in LO-DDGS were not different from the values derived from NO-DDGS. In conclusion, LO-DDGS may have decreased energy compared with NO-DDGS because of its lower fat content. However, oil removal during the production of DDGS may not affect amino acid digestibility.     

The role of muscarinic receptors in the beneficial effects of adenosine against myocardial reperfusion injury in rats

Adenosine, a catabolite of ATP, displays a wide variety of effects in the heart including regulation of cardiac response to myocardial ischemia and reperfusion injury. Nonetheless, the precise mechanism of adenosine-induced cardioprotection is still elusive. Isolated Sprague-Dawley rat hearts underwent 30 min global ischemia and 120 min reperfusion using a Langendorff apparatus. Both adenosine and acetylcholine treatment recovered the post-reperfusion cardiac function associated with adenosine and muscarinic receptors activation. Simultaneous administration of adenosine and acetylcholine failed to exert any additive protective effect, suggesting a shared mechanism between the two. Our data further revealed a cross-talk between the adenosine and acetylcholine receptor signaling in reperfused rat hearts. Interestingly, the selective M(2) muscarinic acetylcholine receptor antagonist methoctramine significantly attenuated the cardioprotective effect of adenosine. In addition, treatment with adenosine upregulated the expression and the maximal binding capacity of muscarinic acetylcholine receptor, which were inhibited by the selective A(1) adenosine receptor antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME). These data suggested a possible functional coupling between the adenosine and muscarinic receptors behind the observed cardioprotection. Furthermore, nitric oxide was found involved in triggering the response to each of the two receptor agonist. In summary, there may be a cross-talk between the adenosine and muscarinic receptors in ischemic/reperfused myocardium with nitric oxide synthase might serve as the distal converging point. In addition, adenosine contributes to the invigorating effect of adenosine on muscarinic receptor thereby prompting to regulation of cardiac function. These findings argue for a potentially novel mechanism behind the adenosine-mediated cardioprotection.     

Crystal structure of human vacuolar protein sorting protein 29 reveals a phosphodiesterase/nuclease-like fold and two protein-protein interaction sites

Vacuolar protein sorting protein 29 (Vps29p), which is involved in retrograde trafficking from prevacuolar endosomes to the trans-Golgi network, performs its biological functions by participating in the formation of a "retromer complex." In human cells, this complex comprises four conserved proteins: hVps35p, hVps29p, hVps26p, and sorting nexin 1 protein (SNX1). Here, we report the crystal structure of hVps29p at 2.1 Angstroms resolution, the first three-dimensional structure of the retromer subunits. This novel structure adopts a four-layered alpha-beta-beta-alpha sandwich fold. hVps29p contains a metal-binding site that is very similar to the active sites of some proteins of the phosphodiesterase/nuclease protein family, indicating that hVps29p may carry out chemically similar functions. Structure and sequence conservation analysis suggests that hVps29p contains two protein-protein interaction sites. One site, which potentially serves as the interface between hVps29p and hVps35p, comprises 5 conserved hydrophobic and 8 hydrophilic residues. The other site is relatively more hydrophilic and may serve as a binding interface with hVps26p, SNX1, or other target proteins.     

Identification of human VPS37C, a component of endosomal sorting complex required for transport-I important for viral budding

Endosomal sorting complex required for transport-I (ESCRT-I) is one of three defined protein complexes in the class E vacuolar protein sorting (VPS) pathway required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. In yeast, ESCRT-I is composed of three proteins, VSP23, VPS28, and VPS37, whereas in mammals only Tsg101(VPS23) and VPS28 were originally identified as ESCRT-I components. Using yeast two-hybrid screens, we identified one of a family of human proteins (VPS37C) as a Tsg101-binding protein. VPS37C can form a ternary complex with Tsg101 and VPS28 by binding to a domain situated toward the carboxyl terminus of Tsg101 and binds to another class E VPS factor, namely Hrs. In addition, VPS37C is recruited to aberrant endosomes induced by overexpression of Tsg101, Hrs, or dominant negative form of the class E VPS ATPase, VPS4. Enveloped viruses that encode PTAP motifs to facilitate budding exploit ESCRT-I as an interface with the class E VPS pathway, and accordingly, VPS37C is recruited to the plasma membrane along with Tsg101 by human immunodeficiency virus, type 1 (HIV-1) Gag. Moreover, direct fusion of VPS37C to HIV-1 Gag obviates the requirement for a PTAP motif to induce virion release. Depletion of VPS37C from cells does not inhibit murine leukemia virus budding, which is not mediated by ESCRT-I, however, if murine leukemia virus budding is engineered to be ESCRT-I-dependent, then it is inhibited by VPS37C depletion, and this inhibition is accentuated if VPS37B is simultaneously depleted. Thus, this study identifies VPS37C as a functional component of mammalian ESCRT-I.     

Genetic control of the opaque-2 gene and background polygenes over some kernel traits in maize (Zea mays L.)

Some kernel traits of agronomical importance in maize are affected by the opaque-2 (o2) gene and background polygenes, which express in different genetic systems such as embryo, endosperm, cytoplasm and maternal plant. A genetic model for seed quantitative traits with the o2 gene effects and polygenic effects as well as their GE interactions was used for protein content, lysine content, oil content and kernel density in maize. The results suggested that the o2 gene was involved in the traits investigated but the effects of the o2 gene were distinctive on various traits. The effects of the o2 gene were large on lysine content and protein content while minor on oil content. There was a substantially wide quantitative variation from polygenes expressing in different genetic systems for the traits evaluated. Significant GE interactions of the o2 gene and background polygenes declared that not only the main effects but also specific expressions depending on environments were responsible for variation of the traits studied. There seemed to have strong maternal heterosis and slight embryo heterosis for kernel density.     

Reactive oxygen species mediate RANK signaling in osteoclasts

RANKL, a member of tumor necrosis factor (TNF) superfamily, regulates the differentiation, activation, and survival of osteoclasts through binding to its cognate receptor, RANK. RANK can interact with several TNF-receptor-associated factors (TRAFs) and activates signaling molecules including Akt, NF-kappaB, and MAPKs. Although the transient elevation of reactive oxygen species (ROS) by receptor activation has been shown to act as a cellular secondary messenger, the involvement of ROS in RANK signaling pathways has been not characterized. In this study, we found that RANKL stimulated ROS generation in osteoclasts. Pretreatment of osteoclasts with the antioxidants N-acetyl-l-cystein and glutathione reduced RANKL-induced Akt, NF-kappaB, and ERK activation. The reduced NF-kappaB activity by antioxidants was associated with decreased IKK activity and IkappaBalpha phosphorylation. In contrast, antioxidants did not prevent TNF-alpha-induced Akt and NF-kappaB activation. Pretreatment with antioxidants also significantly reduced RANKL-induced actin ring formation, required for bone resorbing activity, and osteoclast survival. Taken together, our results suggest that ROS act as mediators in RANKL-induced signaling pathways and cellular events.     

Effect of Hillslope Gradient on Vegetation Recovery on Abandoned Land of Shifting Cultivation in Hainan Island, South China

In the present study, we investigated the effect of hillslope gradient on vegetation recovery on abandoned land of shifting cultivation In Hainan Island, south China, by measuring community composition and structure of 25-year-old secondary forest fallows along a hillslope gradient （up-, middle-, and down-slope position）. A total of 49 733 free-standing woody plant stems higher than 10 cm and belonging to 170 species, 112 genera, and 57 families was found in the three l-hm2 investigation plots. Stem density was highest in the down-slope stand and lowest in the up-slope stand. Species richness and the Shannon-Wiener Index were both highest in the middle-slope stand, and lower In the down-slope and up-slope stands. The recovery forest fallows on different hiUslope positions were all dominated by a few species. The five most abundant species accounted for 70.1%, 58.8%, and 72.9% of total stem densities in stands in the up-, middle-, and down-slope positions, respectively. The five species with the greatest basal areas accounted for 74.5%, 84.3%, and 74.7% of total stem basal area for the up-, middle-, and down-slope positions, respectively. The number of low-density species （stem abundance less than five） Increased from the up-slope position downward. Of the nine local common species among three different functional groups, the short-lived pioneer species dominated the up-slope position, but long-lived pioneer species dominated the middle- and down-slope positions. The climax species of primary tropical lowland rain forest was found in the downslope position. Both the mean diameter at breast height （DBH） and mean height of the trees Increased with decreasing hillslope gradient. The stem density and basal area in different size classes were significantly different in stands In different slope positions. Our results indicated that the rate of secondary succession varies, even over small spatial scales caused by the hlllslope gradient, in early vegetation recovery.