Gene/Protein Disease Symptom Drug Enzyme Compound
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The erythrocytes of 12-month old Sod1 (-/-) mice showed an increased level of reactive oxygen species (ROS), as estimated by the degree of dihydroethidine and dihydrorhodamine oxidation, and the increased level of Heinz bodies. No indices of severe oxidative stress were found in the red blood cells and blood plasma of Sod1 (-/-) mice as judged from the lack of significant changes in the levels of erythrocyte and plasma glutathione, plasma protein thiol and carbonyl groups and thiobarbituric-acid reactive substances in the blood plasma. However, a decreased erythrocyte lifespan, increased reticulocyte count and splenomegaly were noted, indicating the importance of superoxide dismutase for maintaining erythrocyte viability. The levels of erythrocyte ROS and Heinz bodies and the reticulocyte count were indistinguishable in Sod1 (+/+) and Sod1 (+/-) mice, suggesting that a superoxide dismutase activity decrease to half of its normal value may be sufficient to secure the protective effects of the enzyme.
Cell Mol Biol Lett 2009
PMID:The effects of superoxide dismutase knockout on the oxidative stress parameters and survival of mouse erythrocytes. 1883 73

We describe a case of a 24-year-old man with a large anterior mediastinal mass showing a nonseminomatous germ cell tumor then subsequently developed hemophagocytic syndrome involving the bone marrow and liver. During the course of chemotherapy, he developed profound thrombocytopenia, eccymoses, and bleeding. He had moderate splenomegaly and splenectomy was performed to restore adequate hematologic reserve to permit further chemotherapy. The spleen showed marked erythrophagocytosis and markedly atypical histiocytes consistent with malignant histiocytoses. Atypical histiocytes stained positive for CD68, CD163, CD4, CD45 (LCA), and S-100. Cytogenetics studies were negative for i12p. The patient was refractory to therapy and ultimately died 5 months after diagnosis.
Appl Immunohistochem Mol Morphol 2009 Jul
PMID:Malignant histiocytoses/disseminated histiocytic sarcoma with hemophagocytic syndrome in a patient with mediastinal germ cell tumor. 1898 51

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.
Mol Cancer Res 2008 Nov
PMID:Period 2 mutation accelerates ApcMin/+ tumorigenesis. 1901 Aug 25

We have previously reported that disease symptoms can be greatly ameliorated in rodents with adjuvant-induced arthritis (AIA) by first immunizing the rodents against fluorescein and then treating the animals with folate-fluorescein. In this targeted hapten therapy, folate-fluorescein was shown to decorate folate receptor (FR)-expressing activated macrophages with fluorescein (an immunogenic hapten), leading to binding of antifluorescein antibodies and the consequent elimination of the activated macrophages by Fc receptor-expressing immune cells. In the current study, we compare the therapeutic potencies of a variety of FR-targeted haptens in treating the symptoms of AIA in rats. Rats were immunized with either dinitrophenyl (DNP) or trinitrophenyl (TNP) conjugated to keyhole limpet hemocyanin followed by induction of AIA with heat-inactivated Mycobacterium butyricum. Following development of arthritis, rats were treated with one of five folate-hapten conjugates (folate-DNP1, folate-DNP2, folate-DNP3, folate-FITC, or folate-TNP) at two different doses (30 nmol/kg or 200 nmol/kg) 5x/week for 25 days. Symptoms of AIA in treated rats, including paw swelling, arthritis score, splenomegaly, bone erosion, and FR(+) activated macrophage density in inflamed tissues, were quantitated over the course of therapy. Although all folate-hapten conjugates promoted a reduction in disease symptoms, folate-TNP and folate-FITC proved to be more potent than any of the 3 folate-DNP conjugates. We conclude that both folate-TNP and folate-FITC constitute promising haptens for use in FR-targeted immunotherapy of arthritis.
Mol Pharm
PMID:Folate-targeted hapten immunotherapy of adjuvant-induced arthritis: comparison of hapten potencies. 1937 7

beta-Thalassemia is the most common single gene disorder in Iran and more than 25,000 affected individuals have been reported. It has been reported that in patients with beta-thalassemia in the presence of Xmn1 polymorphic site the level of Hb F and (G)gamma: (A)gamma ratio is increased. The prevalence of Xmn1 polymorphic site, (G)gamma: (A)gamma ratio and Hb F in 197 beta-thalassemia major patients from the Kermanshah Province of Iran were studied. The Xmn1 polymorphic site was determined by PCR-RFLP procedure. The levels of (G)gamma and (A)gamma chains were detected by HPLC. The percent of Hb F was determined using electrophoresis method. In beta-thalassemia major patients the frequency of presence Xmn1 was 0.39. The mean of (G)gamma: (A)gamma ratio was found to be 2.5. In the present study it was found that in the presence of Xmn1 polymorphic site (G)gamma percent and (G)gamma: (A)gamma ratio were significantly increased (P = 0.01) and the clinical features such as splenomegaly and bone marrow expansion were significantly improved (P = 0.01). We found that in the presence of Xmn1 polymorphic site on both chromosomes (+/+) the level of Hb F tended to be increased compared to the absence of Xmn1 (-/-). The present investigation has studied the frequency of Xmn1 polymorphic site in beta-thalassemia major patients from Western Iran and has revealed that the presence of this polymorphic site caused a positive influence on Hb F production and the (G)gamma percent which could improve the clinical symptoms of beta-thalassemia patients.
Mol Biol Rep 2010 Jan
PMID:The Xmn1 polymorphic site 5' to the (G)gamma gene and its correlation to the (G)gamma:(A)gamma ratio, age at first blood transfusion and clinical features in beta-thalassemia patients from Western Iran. 1944 45

Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age, 49+/-3.3; range, 20-81 years). The patients were followed for a median of 9.5 years (range, 3-16 years). Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8+/-0.27 g/dL vs. mean recent concentration of 12.6+/-0.37 g/dL, p=0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138+/-13x10(9)/L vs. mean recent count of 138.5+/-18x10(9)/L, p=0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2xnormal (N) vs. mean recent volume of 1.06xN, p=0.27) and 6 of 22 (27%) patients had moderate hepatomegaly (liver volume, 1.25-2.5xN). Spleen volumes remained stable over time (mean baseline spleen volume of 6.6xN vs. mean recent volume of 5.2xN, p=0.5). None of the changes was statistically significant. Four of 20 (20%) patients had moderate splenomegaly (spleen volume, 5-15xN), 2 of 20 (10%) had marked splenomegaly (spleen volume, >or=15xN), and 2 of 22 (9%) had had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 16 of 22 (73%) patients followed by osteopenia in 15 of 22 (68%), Erlenmeyer flask deformity in 13 of 22 (59%), and infarctions in 6 of 22 (27%) patients. We observed that bone disease remained relatively stable over time in most patients, although three patients developed new infarcts over time, one developed an avascular necrosis (AVN), and four had an increase in the degree of osteopenia. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications, including bony disease, may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.
Blood Cells Mol Dis
PMID:The clinical course of untreated Gaucher disease in 22 patients over 10 years: hematological and skeletal manifestations. 1979 65

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase. GD is classically divided into three major phenotypes. The most prevailing form is type 1, which presents with variable hepatosplenomegaly, cytopenia, and/or bone disease. In adult patients with mild manifestations, progress of disease might be slow or even absent. As a consequence, treatment with intravenous enzyme replacement or substrate reduction is not always necessary. In the Netherlands, the follow-up of GD patients is centralized, which allows detailed investigation of untreated patients. A retrospective study was conducted in 18 type 1 GD patients, (2 teenagers: 15 and 16 years of age at first visit) who were not treated for at least one year. The chitotriosidase activity, platelet count, hemoglobin level, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), liver ratio (ml/kg body weight), and spleen volume were recorded. Criteria were developed to score regression, stability or progression of disease. During a mean follow up of 4.5 years (range 1.1-12.2) seven patients (39%) showed spontaneous regression of GD. Eight patients (44%) were stable. Two patients had progressive disease, solely based upon a sustained increase in chitotriosidase activity. A pediatric patient had an increase in splenomegaly but an improvement in bone marrow fat fraction, probably due to aging. Nine patients fulfilled the local criteria to start treatment at first visit, of whom six started treatment within 1.1 to 6.8 years. The other three refused therapy, but nevertheless showed stability or even regression of the disease during a follow up of 4.6, 9.5 and 11.4 years respectively. None of the parameters was predictive of progression or regression of disease. In conclusion, GD in adults can, in some cases, regress spontaneously. No parameters for accurately predicting future disease course exist.
Blood Cells Mol Dis 2010 Mar 15
PMID:Spontaneous regression of disease manifestations can occur in type 1 Gaucher disease; results of a retrospective cohort study. 2007 83

Tumour-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumour progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b(+) and Gr-1(+) cell surface markers remains unclear. Because CD11b(+)Gr-1(+) cells expand during progressive tumour growth, this suggests that tumour-induced events alter signalling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-gamma regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumour-induced CD11b(+)Gr-1(+) cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumour growth. In the 4T1 model, both splenic and bone marrow-derived CD11b(+)Gr-1(+) cells of tumour-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumour-induced CD11b(+)Gr-1(+) cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumour growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b(+)Gr-1(+) cells were significantly lower in dTg mice when compared with single transgenic tumour-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumour-induced development and/or accumulation of CD11b(+)Gr-1(+) cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy.
J Cell Mol Med 2009 Sep
PMID:Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells. 2019 88

Longdan Xiegan Tang (LXT) is a Chinese herbal medicine that is prescribed as an anti-inflammatory aid, a hepato-protectant, and an immunostimulant. In this study, we examined the biological effects of LXT administration in MRL/lpr mice. MRL/lpr mice provide a good model of systemic lupus erythematosus (SLE). These mice develop immunological disturbances and dysregulation in Th1 and Th2 cytokine production. Female mice were randomly separated into two groups. The experimental group received LXT (250 mg/kg/day, po) from 19 to 21 weeks of age. Splenic CD3+CD4+, CD3+CD8+, and CD4+CD25+ T cells were increased in the LXT-administered mice compared to MRL/lpr controls, and this was associated with splenomegaly. There was a marked reduction in IFN-gamma, TNF-alpha, anti-dsDNA antibody, and there were reduced IgG immune complex deposits in the glomeruli. LXT also restored kidney glutathione levels, thereby limiting the toxic effects of the inflammatory mediators iNOS and COX-2, which are overproduced in MRL/lpr mice. Two-dimensional gel electrophoresis was used to analyze proteome changes. LXT protected MRL/lpr mice against developing the lupus syndrome through up-regulation of phosphoglycerate kinase 1 and down-regulation of ferritin light chain 1, selenium-binding protein 2, and alpha-enolase. This study indicates that LXT at this dose and time course of administration was effective in reducing oxidative stress associated with disease progression in MRL/lpr mice. LXT could be useful as adjunctive therapy for reducing distress in SLE.
Int J Mol Med 2010 May
PMID:Longdan Xiegan Tang has immunomodulatory effects on CD4+CD25+ T cells and attenuates pathological signs in MRL/lpr mice. 2037 9

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.
Mol Cancer Ther 2010 Jul
PMID:Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. 2058 63


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