Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells.

Immunotherapy that activates the host immune system to reverse immunosuppression has emerged as a new generation of cancer treatment in both preclinical studies and clinical trials. Although immunotherapy has shown significant achievements in the treatment of various cancers, it faces challenges that limit its further evolution such as poor permeation and modest responsiveness. The development of nanoparticle drug delivery system has provided an opportunity to overcome these drawbacks and to achieve optimized immunotherapy. Based on the research of our group, we here introduce the new strategies being employed using nanoscale intelligent drug delivery systems to enhance the effects of cancer immunotherapy. We also provide a perspective on the further possible application of nanoparticles in more effective antitumor immunotherapy.

Identification of FECH gene multiple variations in two Chinese patients with erythropoietic protoporphyria and a review.

Erythropoietic protoporphyria (EPP), an autosomal dominant disease, is caused by partial deficiency of ferrochelatase (FECH), which catalyzes the terminal step of heme biosynthesis because of loss-of-function mutations in the FECH gene. To date, only a few cases have been described in Asia. In this study, we describe the clinical features of two Chinese patients with EPP, with diagnosis confirmed by the increase of free protoporphyrin in erythrocytes, detection of plasma fluorescence peak at 630-634 nm, and analysis of FECH gene mutations. Using gene scanning, we identified a small deletion in the FECH gene (c.973 delA) in one proband (patient A) and a pathogenic FECH mutation (c.1232 G>T) in the other (patient B) and also observed some nucleotide variations (c.798 C>G, c.921 A>G, IVS1-23 C>T, IVS3+23 A>G, IVS9+35 C>T, and IVS3-48 T>C) in these patients. The family pedigree of patient A was then established by characterization of the genotype of the patient's relatives. We also analyzed the potential perniciousness of the missense mutation with bioinformatic software, Polyphen and Sift. In summary, Chinese EPP patients have similar manifestations to those of Caucasians, and identification of the Chinese FECH gene mutations expands the FECH genotypic spectrum and may contribute to genetic counseling.

Mitochondrial ferritin attenuates ß-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways.

AIMS: Mitochondrial ferritin (MtFt), which was recently discovered, plays an important role in preventing neuronal damage in 6-hydroxydopamine-induced Parkinsonism by maintaining mitochondrial iron homeostasis. Disruption of iron regulation also plays a key role in the etiology of Alzheimer's disease (AD). To explore the potential neuroprotective roles of MtFt, rats and cells were treated with Aß(25-35) to establish an AD model. RESULTS: We report that knockdown of MtFt expression significantly enhanced Aß(25-35)-induced neurotoxicity as shown by dysregulation of iron homeostasis, enhanced oxidative stress, and increased cell apoptosis. Opposite results were obtained when MtFt was overexpressed in SH-SY5Y cells prior to treatment with Aß(25-35). Further, MtFt inhibited Aß(25-35)-induced P38 mitogen-activated protein kinase and activated extracellular signal-regulated kinase (Erk) signaling. INNOVATION: MtFt attenuated Aß(25-35)-induced neurotoxicity and reduced oxidative damage through Erk/P38 kinase signaling. CONCLUSION: Our results show a protective role of MtFt in AD and suggest that regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for AD.

Inhibitory effects of trolox-encapsulated chitosan nanoparticles on tert-butylhydroperoxide induced RAW264.7 apoptosis.

A nanocarrier, namely, hydroxylethyl-chitosan nanoparticles was developed in this research for delivering antioxidants with 6-hydroxy-2, 5, 7, 8-tetra-methylchromane-2-carboxylic acid (trolox) as a model antioxidant. The trolox-encapsulated chitosan nanoparticles (trolox-CS NPs) were prepared by modifying chitosan with epoxyethane, which self-assembled into NPs and entrapped trolox, and then characterized by their size, size distribution, morphology and in vitro trolox release profile. Intracellular trafficking of CS NPs was observed. The anti-oxidant effect and potential mechanism of trolox-CS NPs were subsequently investigated in RAW264.7 cells. The effects of trolox-CS NPs on RAW264.7 cells damaged by tert-butylhydroperoxide (t-BHP) were determined by MTT assay for cell viability, MDA assay for membrane lipid peroxidation, JC-1 probe and Annexin V-FITC/PI double staining for mitochondria membrane potential (MMP) and RAW264.7 apoptosis, respectively. The trolox-CS NPs significantly improved cell viability and reduced MDA content compared with those of cells treated with free trolox. The trolox-CS NPs treatment inhibited MMP collapse and RAW264.7 apoptosis more obviously than free trolox. Molecular basis of apoptosis studied by western blotting revealed that trolox-CS NPs may block mitochondria-mediated apoptosis pathway through up-regulation of Bcl-2 and down-regulation of Bax and inhibiting the activation of pro-caspase 3, PARP and Bid.

Do the mutations of C1GALT1C1 gene play important roles in the genetic susceptibility to Chinese IgA nephropathy?

BACKGROUND: The deficiency of beta1,3 galactose in hinge region of IgA1 molecule played a pivotal role in pathogenesis of IgA nephropathy (IgAN). Cosmc, encoded by C1GALT1C1 gene, was indispensable to beta1,3 galactosylation of IgA1. We designed a serial study to investigate the relationship between the mutations of C1GALT1C1 gene and the genetic susceptibility to IgAN. METHODS: Nine hundred and thirty-eight subjects, including 661 patients with IgAN and 277 healthy controls were enrolled in the study. Firstly, single nucleotide polymorphisms (SNPs) in the promoter region of C1GALT1C1 gene were screened. Then the c.-347-190G>A was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) for further case-control association analysis. Secondly the somatic mutations of DNAs from peripheral blood B lymphocytes were detected in 15 patients and 7 normal controls. RESULTS: No significant association was observed between the different alleles or genotypes of c.-347-190G>A and IgAN. The patients with different genotypes of C1GALT1C1 gene did not significantly associate with clinical manifestations, including hematuria, proteinuria, and serum creatinine of patients with IgAN. There was no somatic mutation detected in total 202 clones of 22 individuals. CONCLUSION: The c.-347-190G>A polymorphism and the somatic mutation of encoding region of C1GALT1C1 gene were not significantly related to the genetic susceptibility to IgAN in Northern Chinese population.

[Influences of MyoG gene on reproductive traits in Jinhua pig].

The genotypes in the second intron and 3' UTR region of myogenin gene in 149 Jinhua pigs (line I, 109; line II, 15; line III, 25) were detected by PCR-RFLP method. The results showed that three genotypes (AA, AB and BB) in the PCR1-MspI-RFLP site were detected and their frequencies were 0.1544, 0.3826, 0.4631, respectively; MM and MN genotypes were found in PCR2-MspI-RFLP site and their frequencies were 0.9953 and 0.0047. The effect of MyoG gene on the reproductive traits was analyzed using SPSS software. Significant associations were found between MyoG locus and total number born (TNB) in first parity (P<0.05), and number born alive (NBA) in the second parity (P<0.05), but no significant associations existed in other parity combinations of TNB, NBA and litter weight birth (LWB) (P<0.05).