NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFß-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

Cell Apoptosis and Autophagy in Renal Fibrosis.

Renal fibrosis is the final common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Autophagy, a highly conserved lysosomal degradation pathway, plays important roles in maintaining cellular homeostasis in all major types of kidney cells including renal tubular cells as well as podocytes, mesangial cells and endothelial cells in glomeruli. Autophagy dysfunction is implicated in the pathogenesis of various renal pathologies. Here, we analyze the pathological role and regulation of autophagy in renal fibrosis and related kidney diseases in both glomeruli and tubulointerstitial compartments. Further research is expected to gain significant mechanistic insights and discover pathway-specific and kidney-selective therapies targeting autophagy to prevent renal fibrosis and related kidney diseases.

Surface ligand controls silver ion release of nanosilver and its antibacterial activity against Escherichia coli.

Understanding the mechanism of nanosilver-dependent antibacterial activity against microorganisms helps optimize the design and usage of the related nanomaterials. In this study, we prepared four kinds of 10 nm-sized silver nanoparticles (AgNPs) with dictated surface chemistry by capping different ligands, including citrate, mercaptopropionic acid, mercaptohexanoic acid, and mercaptopropionic sulfonic acid. Their surface-dependent chemistry and antibacterial activities were investigated. Owing to the weak bond to surface Ag, short carbon chain, and low silver ion attraction, citrate-coated AgNPs caused the highest silver ion release and the strongest antibacterial activity against Escherichia coli, when compared to the other tested AgNPs. The study on the underlying antibacterial mechanisms indicated that cellular membrane uptake of Ag, NAD+/NADH ratio increase, and intracellular reactive oxygen species (ROS) generation were significantly induced in both AgNP and silver ion exposure groups. The released silver ions from AgNPs inside cells through a Trojan-horse-type mechanism were suggested to interact with respiratory chain proteins on the membrane, interrupt intracellular O2 reduction, and induce ROS production. The further oxidative damages of lipid peroxidation and membrane breakdown caused the lethal effect on E. coli. Altogether, this study demonstrated that AgNPs exerted antibacterial activity through the release of silver ions and the subsequent induction of intracellular ROS generation by interacting with the cell membrane. The findings are helpful in guiding the controllable synthesis through the regulation of surface coating for medical care purpose.

In vitro antimicrobial activity of honokiol against Staphylococcus aureus in biofilm mode.

Staphylococcus aureus (S. aureus) can attach to food, host tissues and the surfaces of medical implants and form a biofilm, which makes it difficult to eliminate. The purpose of this study was to evaluate the effect of honokiol on biofilm-grown S. aureus. In this report, honokiol showed effective antibacterial activity against S. aureus in biofilms. S. aureus isolates are capable of producing distinct types of biofilms mediated by polysaccharide intercellular adhesion (PIA) or extracellular DNA (eDNA). The biofilms' susceptibility to honokiol was evaluated using confocal laser scanning microscopy (CLSM) analysis. The transcript levels of the biofilm-related genes, the expression of PIA, and the amount of eDNA of biofilm-grown S. aureus exposed to honokiol were also investigated. The results of this study show that honokiol can detach existing biofilms, kill bacteria in biofilms, and simultaneously inhibit the transcript levels of sarA, cidA and icaA, eDNA release, and the expression of PIA.

Negatively charged silver nanoparticles cause retinal vascular permeability by activating plasma contact system and disrupting adherens junction.

Silver nanoparticles (AgNPs) have been extensively used as antibacterial component in numerous healthcare, biomedical and consumer products. Therefore, their adverse effects to biological systems have become a major concern. AgNPs have been shown to be absorbed into circulation and redistributed into various organs. It is thus of great importance to understand how these nanoparticles affect vascular permeability and uncover the underlying molecular mechanisms. A negatively charged mecaptoundeonic acid-capped silver nanoparticle (MUA@AgNP) was investigated in this work. Ex vivo experiments in mouse plasma revealed that MUA@AgNPs caused plasma prekallikrein cleavage, while positively charged or neutral AgNPs, as well as Ag ions had no effect. In vitro tests revealed that MUA@AgNPs activated the plasma kallikrein-kinin system (KKS) by triggering Hageman factor autoactivation. By using specific inhibitors aprotinin and HOE 140, we demonstrated that KKS activation caused the release of bradykinin, which activated B2 receptors and induced the shedding of adherens junction protein, VE-cadherin. These biological perturbations eventually resulted in endothelial paracellular permeability in mouse retina after intravitreal injection of MUA@AgNPs. The findings from this work provided key insights for toxicity modulation and biomedical applications of AgNPs.

Clinical characteristics and antibiotic resistance in children with invasive Acinetobacter baumannii infection / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics and antibiotic resistance in children with invasive Acinetobacter baumannii infection (IABI).</p><p><b>METHODS</b>A retrospective analysis was performed on the clinical and drug sensitivity data of 52 children with IABI between January 2004 and December 2011.</p><p><b>RESULTS</b>Of the 52 children with IABI, 35 (67%) were less than one year old and 35 (67%) had IABI in the summer and autumn, 19 (37%) of these children were clinically diagnosed with septicemia, 16 (31%) with urinary tract infection, and 12 (23%) with skin and soft tissue infection, and 38 (73%) of them suffered from underlying diseases. The incidence rates of hospital-acquired and community-acquired IABIs were 90% and 10% respectively; 44 cases (85%) were cured or showed improvement in symptoms, and 8 cases (15%) died. All the IAB strains isolated from these children were sensitive to amikacin, 82% of them were sensitive to imipenem, more than 70% were sensitive to fluoroquinolone and to cefoperazone/sulbactam, 13% were sensitive to cefoperazone, 8% were sensitive to aztreonam, 21% developed multidrug resistance, and 17% developed pan-drug resistance.</p><p><b>CONCLUSIONS</b>IABI occurs more frequently in children under one year of age, and most children with IABI have underlying diseases. IABI mainly results in septicemia, urinary tract infection and skin and soft tissue infection and is mostly hospital-acquired. Multi-drug resistance and pan-drug resistance are severe in IAB strains.</p>

Sorption and biodegradation of tetracycline by nitrifying granules and the toxicity of tetracycline on granules.

This paper examines the simultaneous sorption and biodegradation performance of tetracycline (TC) by the nitrifying granular sludge as well as the short-term exposure toxicity of TC. The removal of TC was characterized by a quick sorption and a slow process of biodegradation. The adsorption process fits pseudo-second-order kinetic model, with a complex mechanism of surface adsorption and intra-particle diffusion. Both temperature and mixed liquor suspended solid (MLSS) influenced TC sorption to the granules. TC biodegradation was enhanced with the increase of COD and NH(4)(+)-N concentrations, with except of the NH(4)(+)-N concentrations higher than 150 mg/L. With the ATU addition, TC degradation was weakened remarkably, indicating a synergistic effect of multiple microbes. Results of the short-term exposure (12h) effects showed that the respirometric activities of the microbes decreased greatly. The addition of TC also decreased the rate of NH(4)(+)-N utilization considerably, with the half saturation constant (K(s)) increasing from 297.7 to 347.2 mg/L.