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Biomedical subjects

Kan Yang

Publications and source records attributed to Kan Yang.

At least 19 recordsLinked to original sources
PubMed2006

Monte Carlo simulations of surface energy of the open tetrahedral surface of 2:1-type phyllosilicate.

Monte Carlo simulations were employed to investigate the surface energy of the open tetrahedral surface of 2:1-type phyllosilicate. Argon was selected as the probe molecule. The adsorption isotherm was simulated and the adsorption potential map was calculated. Both the density and energy distributions of adsorbed atoms were derived at different pressures to explore the adsorption mechanism. It is found that there exist two kinds of energetic sites: minima (-15.5 kJ/mol) corresponding to the centers of six-membered rings and platform points (-8.0 kJ/mol) corresponding to the edges and vertexes of hexagons. They are primary and secondary adsorption sites, respectively. The implications for experiments and future studies are discussed. Current results are applicable for understanding surface energy properties of other clay minerals, since they have very similar basal surfaces.

Journal Article↗
PubMed2006

Calcium plus vitamin D alters preneoplastic features of colorectal adenomas and rectal mucosa.

BACKGROUND: Calcium and vitamin D are chemopreventive agents for colorectal neoplasia. Studies of the effects of calcium and vitamin D on early surrogate markers of reduced risk, such as proliferation, have been limited to evaluation of the flat colorectal mucosa. Biologic changes that may occur in colorectal adenomas after chemopreventive regimens have not been reported. METHODS: In the current study, adenomatous polyps were transected, approximately 50% were removed for histologic examination, and the remnants tattooed before the administration of either calcium carbonate (1500 mg 3 times daily) plus vitamin D(3) 400 IU or a placebo for 6 months. At study end, polyp remnants were resected completely and were used for histologic examination. Immunohistochemical staining was performed in both flat mucosa and in polyp tissue. Proliferation was assessed by MIB-1 staining; apoptosis was assessed by terminal deoxyuridine triphosphate-biotin nick-end labeling, BAK, and Bcl-2 staining; and cytokeratin AE1, vitamin D receptor, MUC5AC mucin, and galectin-3 were assessed by immunohistochemistry. RESULTS: Nineteen patients, including 11 patients in the treatment group and 8 patients in the control group, completed the study. Proliferative indices fell both in flat mucosa and in polyps in the treatment group, and there were no significant changes in the control group. Apoptosis and Bcl-2 immunostaining were unchanged in both groups, but the frequency of BAK-immunostained cells in the interior of polyps rose significantly. Vitamin D receptor staining increased slightly and significantly in flat rectal tissue in the treatment group. There were no significant changes in galectin-3 staining, but a striking reduction in MUC5AC mucin staining in polyps was observed after treatment with calcium plus vitamin D. CONCLUSIONS: The administration of a calcium plus vitamin D chemopreventive regimen resulted in several changes in adenomatous tissue that may have contributed to reduced polyp formation.

Adenoma↗
PubMed2006

[Myeloperoxidase in the plasma of patients with acute coronary syndrome].

OBJECTIVE: To determine the diagnostic value and efficacy for risk stratification of myeloperoxidase (MPO) levels in patients with acute coronary syndrome (ACS). METHODS: One hundred and sixty-two patients were enrolled in this study. All patients underwent coronary angiography. They were divided into 3 groups: ACS group (n=54), SAP group (n=54) and control group (n=54). Blood samples were taken from the artery before angiography in all patients and the concentrations of MPO, hsCRP and cTnI were measured. Each subject was asked details of history of hypertension, hyperlipidemia, diabetes and smoking habits. The efficacy of therapy, the cardiovascular events (myocardial infarction, the need for revascularization, or death) were recorded after 6 months of follow-up. RESULTS: The plasma MPO level in ACS group (30.98 ng/mL) was significantly higher than those in the SAP group (14.67 ng/mL) and the control group(14.23 ng/mL)(P<0.01), and the plasma MPO levels in patients of the SAP group and the control group were not significantly different (P=0.74). There was no obvious correlation between the levels of plasma MPO and the serum levels of cTnI, hsCRP,the prevalence of the 4 major risk factors for CHD. Multivariate logistic regression analysis showed that plasma MPO level, free plasma glucose and sex were the significant variables. The risk for subsequent cardiovascular events was higher in the patients with elevated level of MPO. CONCLUSION: Plasma MPO may be a new risk biomarker for ACS and may predict the incidence of subsequent cardiovascular events.

Acute Coronary Syndrome↗
PubMed2005

Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse.

Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair-related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair-mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/- double mutant mice.

The role of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in colon tumorigenesis remains controversial. Notwithstanding evidence that PPAR-gamma ligands impede murine colorectal carcinogenesis, PPAR-gamma agonists have been shown to enhance in vivo tumor formation in mouse models of human colon cancer. Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc1638N/+ Mlh1+/- mice fed a standard AIN-76A diet. We report herein that not only does TGZ enhance carcinogenesis in the large intestine of mutant mice predisposed to intestinal carcinogenesis but TGZ also induces colonic tumors in normal mice without gene targeting or carcinogen administration. This observation indicates that preexisting mutational events are not necessary for induction of colonic tumors by activated PPAR-gamma in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A new integrated method for characterizing surface energy heterogeneity from a single adsorption isotherm.

To characterize surface energy heterogeneity of fine particles, this paper presents an integrated strategy from a single adsorption isotherm. By coupling the well-known integral equation method and derivative isotherm summation (DIS) procedure based on a patchwise model, the newly proposed strategy could calculate adsorption energy distributions (AEDs) for different surface patches. Correspondingly, the surface heterogeneity of materials can be described by weighted summation of patch AEDs, that is, the total AED. The validity of this new method is confirmed by both tests of rutile nanoparticles and multiwalled carbon nanotubes (MWNTs). The total AED obtained by the new method agrees well with the result from solving the integral equation directly, and it shows that AED peaks can be assigned to specific energy patches of real surface exactly. Furthermore, a detailed comparison showed that some artificial oscillation in the results can be identified with the new strategy, and the patches with low area and high surface energy could be characterized as well. In conclusion, this strategy constructs a correspondence between derived AEDs and different patches of real surface, so it will be more effective to understand surface heterogeneity by using the adsorption probe method.

Journal Article↗
PubMed2005

Dietary components modify gene expression: implications for carcinogenesis.

Mouse genetic models that probe important pathways in intestinal cell maturation, such as cell-cycle regulation, apoptosis, and, especially, lineage specific differentiation, have provided profound insight into the underlying mechanisms of intestinal tumor formation and progression. However, a wealth of epidemiological and experimental data indicates that environment, especially the diet, is a principal determinant of relative risk for tumor development. We have demonstrated that even in mouse models in which tumor incidence is strongly initiated by genetic manipulation of genes, such as Apc, p21(WAF1/cip1), and p27(Kip1), a Western-style diet that is high in fat and low in calcium and vitamin D can dramatically increase and accelerate tumor formation. Moreover, experiments show that modulation of calcium and vitamin D levels can substantially influence tumor formation in both the mouse genetic models, as well as in a new dietary model that appears to mimic the development of sporadic colon cancer. Finally, analysis of gene expression profiles provides important insights into how diets may alter metabolic profiles and regulatory pathways that influence probability of tumor formation in the histologically and physiologically normal intestinal mucosa.

Animals↗
PubMed2005

[Proatherogenic effects of immune complexes of human oxLDL in vitro].

OBJECTIVE: To observe the effects of immune complexes (IC) prepared from human oxidized density lipoprotein (oxLDL) antibodies and human oxLDL on the foam cell forming and the macrophage activation, and to further uncover the possible mechanisms of immune complexes contributing to the atherosclerosis occurrence. METHODS: The immune complexes of human oxLDL and purified human oxLDL antibodies were added to culture U937 cells by protocols: polyethylene glycol-precipitated insoluble IC (PEG-IC) and IC immobilized by absorption to red blood cells (RBC-IC). With oxLDL as controls and heat-aggregated gamma globulin as an inhibitor of Fc gamma receptor, we measured the cholesterol ester, total cholesterol of the cellular extracts, and quantified the secreted MMP-1 of supernatants from U937 cells. RESULTS: A significant increase of MMP-1 release [(0.769 +/- 0.030) ng/ml vs (0.513 +/- 0.034) ng/ml, P < 0.01] and a higher level of cholesterol ester accumulation [(20.271 +/- 1.668) microg/mg protein vs (17. 226 +/- 1.298 ) microg/mg protein, P < 0.05] in U937 cells incubated with RBC-IC were observed, compared with those incubated with RBC-oxLDL. However, the above quantative difference between the cholesterol ester accumulation induced by oxLDL and insoluble PEG-IC was even more striking, and cholesterol ester accumulation was dosage-dependent. Heat-aggregated gamma globulin (10 mg/ml) as an inhibitor of Fc gamma receptors competitively inhibited cholesterol ester accumulation and decreased PEG-IC stimulating MMP-1 secretion to 71%. CONCLUSION: Immune complexe of ox-LDL can transform macrophages into foam cells and activted macrophages. The immunological function of oxLDL is involved in the process of atherosclerosis occurrence.

Antibodies↗
PubMed2004

An Msh2 point mutation uncouples DNA mismatch repair and apoptosis.

Mutations in the human DNA mismatch repair gene MSH2 are associated with hereditary nonpolyposis colorectal cancer as well as a significant proportion of sporadic colorectal cancer. The inactivation of MSH2 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of chemotherapeutic agents. Here we show that the DNA repair and DNA damage-induced apoptosis functions of Msh2 can be uncoupled using mice that carry the G674A missense mutation in the conserved ATPase domain. As a consequence, although Msh2(G674A) homozygous mutant mice are highly tumor prone, the onset of tumorigenesis is delayed as compared with Msh2-null mice. In addition, tumors that carry the mutant allele remain responsive to treatment with a chemotherapeutic agent. Our results indicate that Msh2-mediated apoptosis is an important component of tumor suppression and that certain MSH2 missense mutations can cause mismatch repair deficiency while retaining the signaling functions that confer sensitivity to chemotherapeutic agents.

Alanine↗
PubMed2004

Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility.

Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC), and MMR defects are associated with a significant proportion of sporadic cancers. MMR maintains genome stability and suppresses tumor formation by preventing the accumulation of mutations and by mediating an apoptotic response to DNA damage. We describe the analysis of a dominant MSH6 missense mutation in yeast and mice that causes loss of DNA repair function while having no effect on the apoptotic response to DNA damaging agents. Our results demonstrate that MSH6 missense mutations can effectively separate the two functions, and that increased mutation rates associated with the loss of DNA repair are sufficient to drive tumorigenesis in MMR-defective tumors.

Animals↗
PubMed2003

[Renal protective effect of nilestriol in aged women with hypertension].

OBJECTIVE: To investigate the renal protective effect of nilestriol in aged hypertensive women. METHODS: Forty-one aged hypertensive women treated with antihypertensive drugs were randomly divided into two groups. The women in Group A (n = 21) received nilestriol, whereas those in Group B (n = 20) received a placebo for six months. Antihypertensive drugs were unchanged. Twenty-four healthy subjects were set as the normal control group. RESULTS: 1. Before the treatment, the levels of urinary transferrin (TRF), retinol binding protein (RBP), P-selectin, vWF, and ET-1 were significantly higher in the aged hypertensive women than those in the control group. 2. The levels of TRF and RBP significantly decreased in both Group A and Group B after the 6-month treatment, but these levels in Group A were significantly lower than those in Group B (P < 0.05). 3. The levels of P-selectin, vWF, and ET-1 in Group A were significantly lower than those in Group B (P < 0.05-0.01) after the treatment. CONCLUSION: 1. In aged hypertensive women treated with antihypertensive drugs, the renal function is still damaged; 2. Nilestriol can significantly decrease the levels of TRF and RBP; 3. The renal protective effect of nilestriol may be related to the protection of endothelin function and antithrombosis activity.

Aged↗
PubMed2003

Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations.

Sulindac and other NSAIDs have been widely studied as potential chemopreventive agents for colon cancer. Short-term studies have shown adenomatous polyps to regress in patients with familial adenomatous polyposis (FAP). In this study the effect of sulindac on cancer as an endpoint was evaluated in ApcMin mice, a preclinical model of FAP with an Apc mutation in codon 850 that leads to gastrointestinal adenomas and carcinomas. Three groups of mice were studied all of which were fed AIN-76A diet: one group was fed AIN-76A diet alone, a second group received sulindac 200 p.p.m. premixed in the diet and a third group received sulindac 180 p.p.m. added in drinking water. ApcMin mice were killed 9 weeks after feeding was initiated. Mice receiving sulindac developed fewer tumors in the intestine overall; the major decrease in tumor development after sulindac was seen in the small intestine regardless of route of administration. In the large intestine, however, sulindac significantly increased the incidence, multiplicity and volume of tumors in the colon of ApcMin mice, a regional response to sulindac differing from previous reports. Quantitative measurements of apoptosis, Bax and Bcl-xL protein expression in the ApcMin mice revealed the ratio of Bax/Bcl-xL expression and apoptosis increased in the small intestine but decreased in the cecum, consistent with the regional tumorigenesis observed after sulindac. These findings thus suggest involvement of Bax and apoptosis in tumors developing after sulindac treatment in this mouse model.

Animals↗
PubMed2003

Application of gene expression profiling to colon cell maturation, transformation and chemoprevention.

Methods for high-throughput analysis of profiles of gene expression that assay thousands of genes simultaneously are powerful approaches for understanding and classifying cell and tissue phenotype. This includes analysis of normal pathways of cell maturation and their perturbation in transformation, the sensitivity and mechanism of response of normal and tumor cells to physiological and pharmacological agents, and modulation of tumor risk and progression by nutritional factors. However, the complex data generated by such approaches raise difficulties in analysis. We will describe some of the methods we have used in analyzing databases generated in a number of projects in our laboratories. These include: the role of k-ras mutations in colon cell transformation; the role of p21(WAF1/cip1) in intestinal tumor formation and response to sulindac; the development of the absorptive and goblet cell lineages; sensitivity of colonic cells to chemotherapeutic agents; mechanisms that regulate c-myc expression utilizing novel methods of transcriptional imaging; and interaction of nutritional and genetic factors in modulation of intestinal tumor formation.

Animals↗
PubMed2002

Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation.

Mbd4 (methyl-CpG binding domain 4) is a novel mammalian repair enzyme that has been implicated biochemically in the repair of mismatched G-T residues at methylated CpG sites. In addition, the human protein has been shown to interact with the DNA mismatch repair protein MLH1. To clarify the role of Mbd4 in DNA repair in vivo and to examine the impact of Mbd4 inactivation on gastrointestinal (GI) tumorigenesis, we introduced a null mutation into the murine Mbd4 gene by gene targeting. Heterozygous and homozygous Mbd4 mutant mice develop normally and do not show increased cancer susceptibility or reduced survival. Although Mbd4 inactivation did not increase microsatellite instability (MSI) in the mouse genome, it did result in a 2- to 3-fold increase in C-->T transition mutations at CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa. The combination of Mbd4 deficiency with a germ line mutation in the adenomatous polyposis coli (Apc) gene increased the tumor number in the GI tract and accelerated tumor progression. The change in the GI cancer phenotype was associated with an increase in somatic C-->T mutations at CpG sites within the coding region of the wild-type Apc allele. These studies indicate that, although inactivation of Mbd4 does not by itself cause cancer predisposition in mice, it can alter the mutation spectrum in cancer cells and modify the cancer predisposition phenotype.

Animals↗
PubMed2002

Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression.

Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer.

Adenocarcinoma↗
PubMed2002

Colorectal cancer in mice genetically deficient in the mucin Muc2.

The gastrointestinal tract is lined by a layer of mucus comprised of highly glycosylated proteins called mucins. To evaluate the importance of mucin in intestinal carcinogenesis, we constructed mice genetically deficient in Muc2, the most abundant secreted gastrointestinal mucin. Muc2-/- mice displayed aberrant intestinal crypt morphology and altered cell maturation and migration. Most notably, the mice frequently developed adenomas in the small intestine that progressed to invasive adenocarcinoma, as well as rectal tumors. Thus, Muc2 is involved in the suppression of colorectal cancer.

Adenocarcinoma↗