Aims
This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice ...and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans.
Methods
Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β‐hydroxysteroid‐dehydrogenase‐1 (HSD‐1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4–6 weeks. The effects on bw, IR and plasma and liver lipids were assessed.
Results
Rosiglitazone, liraglutide and HSD‐1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD‐1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high‐density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin.
Conclusions
We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non‐alcoholic fatty liver disease (NAFLD).
p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance ...of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.
Tumor necrosis factor-alpha (TNFalpha) is a pleiotropic cytokine exerting both inflammatory and cell death modulatory activity, and is thought to play a role in the pathogenesis of atherosclerosis. ...Studies in mice indicated that TNFalpha affects atherosclerosis minimally or not under conditions that allow fatty streak formation. Here, we examined the possible role of TNFalpha in advanced and complex atherosclerotic lesions.
To induce atherosclerosis, TNFalpha-deficient (Tnf-/-) APOE*3-Leiden and control APOE*3-Leiden only mice were fed a cholesterol-rich diet. Comparable levels of plasma cholesterol and triglycerides and the systemic inflammatory parameters, serum amyloid A and soluble intercellular adhesion molecule-1 were found in APOE*3-LeidenTnf-/- and control mice. Although absence of TNFalpha did not affect the quantitative area of atherosclerosis, APOE*3-LeidenTnf-/- mice had a higher relative number of early lesions (46.1% vs. 21.4%) and a lower relative number of advanced lesions (53.9% vs. 78.6%, P=0.04). In addition, the advanced lesions in APOE*3-LeidenTnf-/- mice showed less necrosis (9.9+/-12.1% vs. 23.4+/-19.3% of total lesion area, P=0.04) and an increase in apoptosis (1.5+/-1.5% vs. 0.4+/-0.6% of total nuclei, P=0.03).
Our data indicate that TNFalpha stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis.
Aims
This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the
MetS
in
APOE
*
3Leiden
.humanCholesteryl Ester Transfer Protein (
E3L
.
CETP
) ...mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans.
Methods
Male obese,
IR
and dyslipidemic
E3L
.
CETP
mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β‐hydroxysteroid‐dehydrogenase‐1 (
HSD
‐1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4–6 weeks. The effects on bw,
IR
and plasma and liver lipids were assessed.
Results
Rosiglitazone, liraglutide and
HSD
‐1 inhibitor significantly decreased glucose and insulin levels or
IR
. Liraglutide and
HSD
‐1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high‐density lipoprotein (
HDL
) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin.
Conclusions
We conclude that the
E3L
.
CETP
mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect
IR
, diabetic dyslipidemia and non‐alcoholic fatty liver disease (
NAFLD
).
The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both ...cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE-deficient mice with a macrophage-restricted deletion of Rb (Rbdel mice) and control littermates (Rbfl mice). After 12 wk feeding a cholesterol-rich diet, the Rbdel mice showed a 51% increase in atherosclerotic lesion area with a 39% increase in the relative number of advanced lesions. Atherosclerotic lesions showed a 13% decrease in relative macrophage area and a 46% increase in relative smooth muscle cell area, reflecting the more advanced state of the lesions. The increase in atherosclerosis was independent of in vitro macrophage modified lipoprotein uptake or cytokine production. Whereas macrophage-restricted Rb deletion did not affect lesional macrophage apoptosis, a clear 2.6-fold increase in lesional macrophage proliferation was observed. These studies demonstrate that macrophage Rb is a suppressing factor in the progression of atherosclerosis by reducing macrophage proliferation.--Boesten, L. S. M., Zadelaar, A. S. M., van Nieuwkoop, A., Hu, L., Jonkers, J., van de Water, B., Gijbels, M. J. J. van der Made, I., de Winther, M. P. J., Havekes, L. M., van Vlijmen, B. J. M. Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice.
The oncoprotein bcl-2 can be expressed in malignant plasma cells and might play a role in the prevention of corticosteroid-mediated apoptosis, thereby prolonging survival of the myeloma cells. We ...retrospectively investigated whether bcl-2 expression in bone marrow plasma cells measured by two-color fluorescence for immunoglobulin light chains would be related to survival duration in patients suffering from multiple myeloma. In all patients the large majority of plasma cells expressed bcl-2 (median 91%, range 74-100%). Contrary to our expectations, a tendency was observed toward higher percentages bcl-2+ plasma cells in patients with a long survival (more than 5 years, n = 9) vs patients who died from refractory myeloma within a year of diagnosis (n = 7). This tendency was found even when analysis was extended to include four patients in the short diagnosis group (n = 11) who had received chemotherapy prior to bone marrow examination.
To determine the maturation arrest of the neoplastic cells of hairy-cell leukemia (HCL) and the spectrum of the surface markers on these cells, a series of 51 patients with this disease was studied. ...The cells of all but two of the patients showed monoclonal surface Ig with respect to light chains. In about one-third of the cases, only γ heavy chain determinants were present on the cells; the majority carried multiple heavy chain determinants as documented by the application of different fluorochromes. Two patients each showed two different clones of cells, both of the same light chain type. In one of these two patients, two paraproteins were present in the serum. Intracyto-plasmic Ig was found in only 4 of 39 cases, in all instances being IgM. All cases studied concerned cells with FcIgG receptors; however, the density of this receptor varied. FcIgM receptors also showed a spectrum of density, with some cases showing very few FclgM-positive cells. Receptors for C3 were not observed on the hairy cells. Serum immunoglobulin levels were normal or increased. Paraproteins were found in the sera of 4 of 38 patients. These data suggest that HCL is a neoplasm of B lymphocytes. The neoplastic cells are probably arrested at a more mature stage than the cells of chronic lymphocytic leukemia. The multiple isotypes on the cells indicate a block at the “switch” phase from the small μ-carrying lymphocyte to the larger Ig-producing lymphocyte or plasma cell.
Here we describe a means to conditionally modify genes at a predefined and localized region of the vasculature using a perivascular drug delivery device (PDD). A 4-hydroxytamoxifen (4-OHT)-eluting ...PDD was applied around the carotid or femoral artery of a mouse strain carrying both the tamoxifen-inducible and smooth muscle cell (SMC)-specific Cre-recombinase (SM-Cre-ER(T2)) transgene and a stop-floxed beta-galactosidase gene in the Rosa26 locus: the SM-CreER(T2)(ki)/rosa26 mouse. A dose and time curve of 0-10% (w/w) 4-OHT and 0-14 days application of the PDD in SM-CreER(T2)(ki)/rosa26 mice showed optimal gene recombination at 1% (w/w) 4-OHT loading at 7 days post application (carotid artery 2.4+/-1.8%; femoral artery 4.0+/-3.8% of SMCs). The unique 4-OHT-eluting PDD allowed us to achieve SMC-specific recombination in the same order of magnitude as compared to systemic tamoxifen administration. In addition, recombination was completely confined to the PDD-treated vessel wall segment. Thus, local application of a 4-OHT-eluting PDD results in vascular SMC-specific Cre-mediated recombination in SM-CreER(T2)(ki)/rosa26 mice without affecting additional SMCs.
One of the unexplained features of human IgD is its preferential expression with either kappa or lambda light chains in different situations. While the membrane IgD on B lymphocytes shows a ...predominance of the kappa type, about 90% of all known IgD myeloma proteins and 87% of normal IgD producing plasma cells in spleens of healthy individuals were shown to belong to the lambda type. Very little is known of the kappa/lambda light chain distribution of normal polyclonal IgD in the serum and in the bone marrow plasma cells. In this study, the kappa/lambda representation of IgD in bone marrow plasma cells and in the serum of 25 adult persons (two healthy and 23 suffering from various nonmalignant diseases) was investigated. The kappa/lambda ratio of IgD+ bone marrow plasma cells showed a large variation among the individuals of this group, in 84% of the cases being below 1.0. While about 1/3 of the investigated subjects had 80% or more of IgD of the lambda type (kappa/lambda ratio below 0.2), most showed a kappa/lambda ratio of IgD higher than that, with four persons exhibiting a clear cut predominance of IgD of the kappa type. A positive correlation (Spearman's correlation co-efficient, P = 0.005) between the percentages of IgD+ plasma cells and their kappa/lambda ratio was found. Semiquantitative evaluation of the kappa/lambda composition within the serum IgD by immunoselection was in agreement with the kappa/lambda ratio of IgD+ plasma cells in all individual cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A patient with IgA lambda multiple myeloma (MM) developed plasma cell leukemia (PCL), presenting as oculomotor nerve palsy. The cerebrospinal fluid (CSF) contained plasma cells, which double stained ...with fluoresceinated anti‐IgA and anti‐lambda antisera. The palsy was most probably due to meningeal myelomatosis. The neurologic disorder appeared to be refractory to the therapy used, although plasma cells disappeared from the peripheral blood. Secondary plasma cell leukemia is a rare complication of MM, usually occurring in the terminal stage of the disease. Those patients may be eligible for central nervous system (CNS) prophylaxis, as is commonly performed in patients with other types of leukemia.
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