Xuelai Liu

Silver nanoparticles—the real “silver bullet” in clinical medicine?

The use of silver nanoparticles has become more widespread in our society. While many believe that silver can be extremely useful in clinical medicine, firm evidence is still lacking. Thus, we present here a review of their current use in clinical medicine.

Silver Nanoparticles Mediate Differential Responses in Keratinocytes and Fibroblasts during Skin Wound Healing

With advances in nanotechnology, pure silver has been recently engineered into nanometer‐sized particles (diameter <100u2005nm) for use in the treatment of wounds. In conjunction with other studies, we previously demonstrated that the topical application of silver nanoparticles (AgNPs) can promote wound healing through the modulation of cytokines. Nonetheless, the question as to whether AgNPs can affect various skin cell types—keratinocytes and fibroblasts—during the wound‐healing process still remains. Therefore, the aim of this study was to focus on the cellular response and events of dermal contraction and epidermal re‐epithelialization during wound healing under the influence of AgNPs; for this we used a full‐thickness excisional wound model in mice. The wounds were treated with either AgNPs or control with silver sulfadiazine, and the proliferation and biological events of keratinocytes and fibroblasts during healing were studied. Our results confirm that AgNPs can increase the rate of wound closure. On one hand, this was achieved through the promotion of proliferation and migration of keratinocytes. On the other hand, AgNPs can drive the differentiation of fibroblasts into myofibroblasts, thereby promoting wound contraction. These findings further extend our current knowledge of AgNPs in biological and cellular events and also have significant implications for the treatment of wounds in the clinical setting.

Modulation of collagen alignment by silver nanoparticles results in better mechanical properties in wound healing

UNLABELLEDnOur previous study has revealed that silver nanoparticles (AgNPs) have potential to promote wound healing by accelerated re-epithelization and enhanced differentiation of fibroblasts. However, the effect of AgNPs on the functionality of repaired skin is unknown. The aim of this study was to explore the tensile properties of healed skin after treatment with AgNPs. Immunohistochemical staining, quantitative assay and scanning electron microscopy (SEM) were used to detect and compare collagen deposition, and the morphology and distribution of collagen fibers. Our results showed that AgNPs improved tensile properties and led to better fibril alignments in repaired skin, with a close resemblance to normal skin. Based on our findings, we concluded that AgNPs were predominantly responsible for regulating deposition of collagen and their use resulted in excellent alignment in the wound healing process. The exact signaling pathway by which AgNPs affect collagen regeneration is yet to be investigated.nnnFROM THE CLINICAL EDITORnThe aim of this study was to explore the tensile properties of healed skin after treatment with AgNPs. These nanoparticles improved tensile properties and led to better fibril alignments in repaired skin, with a close resemblance to normal skin. The exact signaling pathway by which AgNPs affect collagen regeneration is yet to be investigated.

Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2

Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 x 10(-9). The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.

ω-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes.

OBJECTIVEnLong-term total parenteral nutrition (TPN) in children is often complicated by parental nutrition-associated liver disease and may even lead to liver failure. Recently, the addition of ω-3 fatty acids to TPN has been shown to reduce the risk of parental nutrition-associated liver disease. The purpose of this study was to explore the anti-inflammatory effects of ω-3 fatty acids (eicosapentaenoic acid [EPA]) to demonstrate the protection of the liver against hepatic steatosis and damage.nnnMATERIALS AND METHODSnLipopolysaccharide (LPS) and prostaglandin E(2) (PGE(2)) were used to stimulate human macrophages and hepatocytes (THLE-3) to induce in vitro inflammatory condition. The cells were then incubated with either ω-3 (EPA) or ω-6 (arachidonic acid) fatty acids. Supernatants were collected at different time points for the measurement of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) using enzyme-linked immunosorbent assay. Furthermore, pretreated macrophages by LPS stimulation and after incubation with EPA were added to prestimulated hepatocytes for the subsequent measurement of cytokine response.nnnRESULTSnEicosapentaenoic acid effectively reduced LPS-induced or PGE(2)-induced TNF-α and IL-6 expression, and increased IL-10 expression significantly when compared with arachidonic acid. Furthermore, supernatant collected after co-culturing EPA with macrophages also suppressed the levels of TNF-α and IL-6 in hepatocytes. This would suggest that EPA not only had an anti-inflammatory effect on macrophages and hepatocytes directly, it could indirectly reduce hepatocyte inflammation through activated macrophages.nnnCONCLUSIONSnThe addition of ω-3 fatty acids in TPN suppresses the inflammatory response via direct and indirect routes. The findings may help explain the clinical benefits of EPA in pediatric patients receiving long-term TPN.

Mutations in the NRG1 gene are associated with Hirschsprung disease.

Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (pxa0=xa00.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1.

Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation

Background Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform. Methods We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model. Results We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity. Conclusion This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy.

Genome-wide copy number analysis uncovers a new HSCR gene: NRG3

Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (pu200a=u200a1.50×10−5), particularly for those encompassing genes (pu200a=u200a5.00×10−6). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (pu200a=u200a1.64×10−3). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined pu200a=u200a3.36×10−5) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR–associated syndromes showed that while syndromic–HSCR patients carried significantly longer CNVs than the non-syndromic or controls (pu200a=u200a1.50×10−5), non-syndromic patients were enriched in CNV number when compared to controls (pu200a=u200a4.00×10−6) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.

Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model

UNLABELLEDnThe potential use of osteo-conducive biomaterials in the promotion of bone fracture healing has attracted wide attention. This study investigated if silver nanoparticles (AgNps) could promote the proliferation and osteogenesis of mesenchymal stem cells (MSCs), and improve bone fracture healing. We showed that AgNps promoted MSCs proliferation and osteogenic differentiation in vitro. Using a mouse femoral facture model, AgNps encapsulated in collagen promoted the formation of fracture callus, and induced early closure of the fracture gap. AgNps may promote the formation of the callus and the subsequent end joining of the fracture bone via multiple routes: (i) chemo-attraction of MSCs and fibroblasts to migrate to the fracture site; (ii) induction of the proliferation of MSCs; (iii) induction of osteogenic differentiation of MSCs via induction/activation of TGF-β/BMP signaling in MSCs. We concluded that AgNps might be beneficial as an adjunct treatment for bone fracture healing clinically.nnnFROM THE CLINICAL EDITORnSilver nanoparticles are widely used in wound management in the clinical setting. In this article, the authors demonstrated a novel application in that these nanoparticles were efficient in promoting osteoblastic differentiation in both in-vitro and in-vivo studies. The findings may provide a new treatment direction for bone fracture in the future.

Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

BACKGROUND & AIMSnBiliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA.nnnMETHODSnWe genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed.nnnRESULTSnThe combined BA-association p-value of the GWAS SNP (rs17095355) achieved 6.06×10(-10). Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [p=5.32×10(-11); odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62)]. Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of synthetic association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n=36; p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity.nnnCONCLUSIONSnCommon genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population.