Biomedical subjects

Qingzhong Kong

Publications and source records attributed to Qingzhong Kong.

9 recordsLinked to original sources

PubMed2006

Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains.

Aggregated prion protein (PrPSc), which is detergent-insoluble and partially proteinase K (PK)-resistant, constitutes the major component of infectious prions that cause a group of transmissible spongiform encephalopathies in animals and humans. PrPSc derives from a detergent-soluble and PK-sensitive cellular prion protein (PrPC) through an alpha-helix to beta-sheet transition. This transition confers on the PrPSc molecule unique physicochemical and biological properties, including insolubility in nondenaturing detergents, an enhanced tendency to form aggregates, resistance to PK digestion, and infectivity, which together are regarded as the basis for distinguishing PrPSc from PrPC. Here we demonstrate, using sedimentation and size exclusion chromatography, that small amounts of detergent-insoluble PrP aggregates are present in uninfected human brains. Moreover, PK-resistant PrP core fragments are detectable following PK treatment. This is the first study that provides experimental evidence supporting the hypothesis that there might be silent prions lying dormant in normal human brains.

Animals↗

PubMed2006

Cell brain: insight into hepatocarcinogenesis.

Although great effort has been made, the understanding of the mechanisms of hepatocarcinogenesis is still limited. Among all the related hypotheses, the cell brain theory, which emphasized the integrate roles of the complex consisting of centrosome, the embedded centrioles and connecting microtubules (MTs) and interpreted cancer as a cell brain illness rather than a genetic disease, emerges to be more logic and recognizable. According to cell brain theory, all the cellular procedures are coordinated as a whole by the "brain" of a cell determining a cell's fate. Structural and functional abnormalities in the cell brain may result in unequal or multipolar segregation of the chromosomes, thereby causing cell cycle disorder, centrosome amplification, and genomic instability. Although there lacking of direct evidence associating cell brain defects and hepatocarcinogenesis, latest understanding of the roles of the cells brain in cell control does teach us that any defects in the cell brain may contribute to hepatocarcinogenesis. Briefly, more than 100 key proteins involved in DNA synthesis, DNA repair, cell cycle, and apoptosis have been localized to the cell brain. Specifically, more and more novel proteins associated with centrosome such as centrin, centriolin and cenexin are located in the centriole, a core component of cenrtrosome. Aberrant phosphorylation of these proteins and/or mutation of the coding genes may inevitably cause supernumerary centrioles and/or excess pericentriolar material. Modifications of any MT proteins such as tyrosinated tubulin (Tyr-tubulin), detyrosinated tubulin (Glu-tubulin) and Delta2-tubulin may change the structure and function of MTs, thereby interfering with G1 phase progression, altering the dynamics of some key proteins, and mis-regulating signal transduction and transcription. Although little work has been done, we intend to believe, based on the latest understanding of the novel roles of the cell brain in cell control, that defects in any part of the cell brain either in the structure or in the function may result in changes of the genes, eventually leading to the development of liver cancer, which is discussed in this paper and is expected to be helpful in shedding light on the often paradoxical observations seen in the development of cancer, including HCC. It also teaches us that when treating cancerous problems therapeutically or prophylactically, great attention should be given to the centrosome/cell brain, instead of gene alone. More specifically, the centrosome-centered cell brain may come to be novel targets in the treatment of cancer including HCC.

Animals↗

PubMed2006

Gerstmann-Sträussler-Scheinker: a new phenotype with 'curly' PrP deposits.

Gerstmann-Sträussler-Scheinker (GSS) is a hereditary prion disease typically associated with prion protein (PrP)-containing plaques. The protease-resistant, scrapie PrP (PrPSc) is represented by internal fragments, whereas the C-terminal fragments associated with the other prion diseases are generally underrepresented. Different histopathologic and PrPSc features associated with at least 13 PrP gene (PRNP) mutations have been described in GSS. We report the histopathology and PrP characteristics in a father and son carrying a mutation at PRNP codon 187 that substitutes histidine (H) with arginine (R) and is coupled with valine (V) at position 129 (H187R-129V). The PrP plaques were present in both cases but with different structure and topography and minimal spongiform degeneration. A distinctive, "curly" PrP immunostaining was prominent in one case. The protease-resistant PrPSc differed in amount in the 2 cases, possibly depending on whether plaques or the curly immunostain was present. Two protease-resistant PrP fragments of 14 kDa and 7 kDa with, in at least one case, N-terminus between residues 90-99 and 82-90, respectively, codistributed with the plaques, whereas only very small amounts of the PK-resistant PrP were present in the curly staining regions. PK-resistant PrP recovered from the plaque and curly staining regions appeared to be full length.

Adult↗

PubMed2006

RNAi: a novel strategy for the treatment of prion diseases.

Prion disease refers to a group of fatal transmissible neurodegenerative diseases for which no pharmacological treatment is available. The cellular prion protein (PrP(C)) is required for both prion replication and pathogenesis, and reducing PrP(C) levels has been shown to extend survival time after prion infection. RNA interference (RNAi) is a sequence-specific posttranscriptional gene silencing mechanism. In this issue of the JCI, Pfeifer et al. report that lentivector-mediated RNAi significantly reduced neuronal PrP(C) expression; effectively suppressed accumulation of the infectious protease-resistant form of PrP (PrP(Sc)) in a persistently infected neuroblastoma cell line; and markedly slowed the progression of prion disease in a unique chimeric mouse model (see the related article beginning on page 3204). These findings indicate that lentivector-mediated RNAi could, in principle, be developed for the therapy of prion disease.

Animals↗

PubMed2005

Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: comparative analysis of the scrapie prion protein.

Chronic wasting disease (CWD), a transmissible prion disease that affects elk and deer, poses new challenges to animal and human health. Although the transmission of CWD to humans has not been proven, it remains a possibility. If this were to occur, it is important to know whether the "acquired" human prion disease would show a phenotype including the scrapie prion protein (PrP(Sc)) features that differ from those associated with human sporadic prion disease. In this study, we have compared the pathological profiles and PrP(Sc) characteristics in brains of CWD-affected elk and deer with those in subjects with sporadic Creutzfeldt-Jakob disease (CJD), as well as CJD-affected subjects who might have been exposed to CWD, using histopathology, immunohistochemistry, immunoblotting, conformation stability assay, and N-terminal protein sequencing. Spongiform changes and intense PrP(Sc) staining were present in several brain regions of CWD-affected animals. Immunoblotting revealed three proteinase K (PK)-resistant bands in CWD, representing different glycoforms of PrP(Sc). The unglycosylated PK-resistant PrP(Sc) of CWD migrated at 21 kDa with an electrophoretic mobility similar to that of type 1 human PrP(Sc) present in sporadic CJD affecting subjects homozygous for methionine at codon 129 (sCJDMM1). N-terminal sequencing showed that the PK cleavage site of PrP(Sc) in CWD occurred at residues 82 and 78, similar to that of PrP(Sc) in sCJDMM1. Conformation stability assay also showed no significant difference between elk CWD PrP(Sc) and the PrP(Sc) species associated with sCJDMM1. However, there was a major difference in glycoform ratio of PrP(Sc) between CWD and sCJDMM1 affecting both subjects potentially exposed to CWD and non-exposed subjects. Moreover, PrP(Sc) of CWD exhibited a distinct constellation of glycoforms distinguishable from that of sCJDMM1 in two-dimensional immunoblots. These findings underline the importance of detailed PrP(Sc) characterization in trying to detect novel forms of acquired prion disease.

Aged↗

PubMed2005

Tetrazolium violet induces G0/G1 arrest and apoptosis in brain tumor cells.

Tetrazolium violet (TV), a potent anticancer agent, has been shown to induce cell growth-inhibition in tumor cells. However, the related mechanism has not been revealed yet. In this report we assessed the influence of TV on cell growth and cell cycle in brain tumor cells. Treatment of C6 tumor cells with TV (5-15 microM for 24-72 h) resulted in a growth inhibition in a dose and time-dependent manner and G0/G1 phase arrest, determined by flow cytometry analysis. These effects were accompanied by apoptosis other than necrosis, evidenced by nuclear condensation, terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and trypan blue exclusion assay plus lactate dehydrogenase (LDH) release assay. Treatment of cells with TV at 15 microM for 24 h resulted in an increase in the activity of caspase-3, evidenced by colorimetric assay, and a dramatic up-regulation of p53, accompanied with a significant increase of Bax/Bcl-2 ratio, as evidenced by immunofluorescence assay. These results suggest that TV induces growth inhibition of C6 cells through p53-midiated apoptotic pathway and G0/G1 checkpoint mechanism. Although detailed mechanisms remain to be explored, selective blockage of tumor cells in G0/G1 phase accompanied by p53-associated apoptosis makes tetrazolium violet a promising anticancer agent, meriting further investigations.

Antineoplastic Agents↗

PubMed2005

Chronic wasting disease of elk: transmissibility to humans examined by transgenic mouse models.

Chronic wasting disease (CWD), a prion disease affecting free-ranging and captive cervids (deer and elk), is widespread in the United States and parts of Canada. The large cervid population, the popularity of venison consumption, and the apparent spread of the CWD epidemic are likely resulting in increased human exposure to CWD in the United States. Whether CWD is transmissible to humans, as has been shown for bovine spongiform encephalopathy (the prion disease of cattle), is unknown. We generated transgenic mice expressing the elk or human prion protein (PrP) in a PrP-null background. After intracerebral inoculation with elk CWD prion, two lines of "humanized" transgenic mice that are susceptible to human prions failed to develop the hallmarks of prion diseases after >657 and >756 d, respectively, whereas the "cervidized" transgenic mice became infected after 118-142 d. These data indicate that there is a substantial species barrier for transmission of elk CWD to humans.

Animals↗

PubMed2005

Does the cell-brain theory work in explaining carcinogenesis?

As a major microtubule-organizing center, the centrosome, together with the embedded centrioles and connecting filaments (or microtubules), has lately been proposed to be the "brain" of a cell. Although there are a lot of works to be done to test this hypothesis, emerging data have suggested that this centrosome-centered "cell brain" is playing increasingly important roles in cell control. Genes seem not to tell the whole story, despite the commonly held view that genetic alteration is the cause of most medical problems including cancer development. Although the mechanisms through which gene expression and protein synthesis are regulated remain to be studied, current advances in our understanding of the roles of the centrosome in the regulation of DNA synthesis, DNA repair, cell cycle, apoptosis and in the maintenance of genetic stability are challenging our tradition thoughts. Genetic alterations may be repaired by the centrosome-centered "cell brain"-mediated self-defense, but the cell brain defects intend to cause genetic alterations, which, in turn, may result in cancer development. Further understanding of the roles of the centrosome/cell brain in these and other new aspects are becoming very helpful in comprehending why and how medical problems including tumors develop. Meanwhile, it suggests that great attention should be given to the centrosome/cell brain, instead of gene alone when treating medical problems, which is discussed in this paper on the basis of cell brain theory and may prove helpful in shedding light on the often paradoxical observations seen in cell control, particularly in cancer development.

Apoptosis↗

PubMed2003

Sporadic and familial CJD: classification and characterisation.

Prion diseases are unique transmissible neurodegenerative diseases that have diverse phenotypes and can be familial, sporadic, or acquired by infection. Recent findings indicate that the PrP genotype and the PrP(Sc) type have a major influence on the disease phenotype in both sporadic and familial human prion diseases. This review attempts to classify and characterise sporadic and familial Creutzfeldt-Jakob disease (CJD) as a function of these two disease determinants. Based on the genotype at codon 129 on both PRNP alleles, the size of protease resistant PrP(Sc) fragments and disease phenotype, we divide sporadic CJD into six subtypes: sCJDMM1/sCJDMV1, sCJDVV2, sCJDMV2, sCJDMM2, sCJDVV1, and sporadic fatal insomnia (sFI). Familial CJD is classified into many haplotypes based on the PRNP mutation and codon 129 (and other polymorphic codons) on the mutant allele. The clinical and pathological features are summarised for each sporadic CJD subtype and familial CJD haplotype.

Adolescent↗