Restoration of Peroxiredoxins and Catalase Is Closely Correlated with the Level of Philadelphia Chromosome during Imatinib Therapy in CML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4539-4539
Author(s):  
Kyoung-Eun Lee ◽  
Hyun-Ae Woo ◽  
Seoug-Ha Yang ◽  
Jung-Won Huh ◽  
Moon Young Choi ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Philadelphia Chromosome ◽  
Bone Marrow Aspiration ◽  
New Drugs ◽  
Aberrant Expression ◽  
Abl Kinase ◽  
Normal Individuals

Abstract Background: Several investigators have recently shown that activated growth factor receptors increase the relative levels of intracellular ROS and that bcr/abl kinase induces the production of ROS in hematopoietic cells. In addition, bcr-abl kinase induces self-mutagenesis via ROS to encode IM resistance. Meanwhile, two members of the peroxiredoxin family, Prx 1 or Prx 2, efficiently lowered the intracellular level of H2O2 and blocked the induction of apoptosis by ceramide, suggesting that the Prx enzymes contribute to intracellular signaling by removing H2O2. In this study, we investigated the changse in the levels of H2O2-removing enzymes like Prxs, glutathione peroxidase 1 (Gpx1), and catalase during Imatinib (IM) therapy in CML. Methods: Mononuclear cells(MNC) were isolated by standard Ficoll-Hypaque from the bone marrow aspiration at the time of diagnosis and during treatment with IM (Gleevec, Novartis, East Hanover, NJ). Standard cytogenetics analysis and RT-PCR for Philadelphia chromosomes were performed. For immunoblot analysis of antioxidant enzymes, cell lysates were fractionated by SDS-PAGE, and the separated proteins were transferred electrophoretically to a nitrocellulose membrane (Protran, Germany) and were probed with antibodies specific for Prx I, II, VI, GPx1, or catalase (AbFrontier, South Korea). Results: Samples from the diagnosis CML patients showed significantly decreased levels of Prx I, Prx II, Prx IV, and Gpx I, but also revealed an increased level of catalase. Especially prominent was the diminished ratio of Prx II to catalase in CML patients when compared with those of normal individuals. As the level of Philadelphia chromosomes decreased to that of normal individuals as the result of IM treatment, the expression levels of Prx(s) (P=0.018) and catalase (P=0.009) were restored to the levels of normal individuals. Conclusions: Decreased Prx 2 and elevated catalase levels at the time of diagnosis are closely correlated with the elevated bcr/abl kinase level in CML. The aberrant expression of those antioxidant enzymes returned to normal with IM treatment. Now, we will attempt to develop these method(s) to assess the changes of Prx(s) and catalase on the single cell level using immunohistochemistry with monoclonal Ab(s). Understanding the molecular mechanisms of changes on antioxidant might be a potent tool in developing more effective new drugs in CML.

scholarly journals mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 924
Author(s):  
Federica Ungaro ◽  
Valentina Garlatti ◽  
Luca Massimino ◽  
Antonino Spinelli ◽  
Michele Carvello ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Leukocyte Trafficking ◽  
Lymphatic Endothelium ◽  
Chronic Inflammatory Condition

Crohn’s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit α (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD.

The Level of Peroxiredoxin and Catalase On Single Cell Level Is Correlated with the Positivity of Ph Chromosome in the Bone Marrow of CML Patients During Imatinib Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1114-1114
Author(s):  
Kyoung-Eun Lee ◽  
Hyun Ae Woo ◽  
Seung Ha Yang ◽  
Jung-Won Huh ◽  
Jee-Young Ahn ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Single Cell ◽  
Cancer Cells ◽  
Blast Crisis ◽  
Redox Signaling ◽  
Single Cell Level ◽  
Newly Diagnosed ◽  
Cell Level ◽  
Aberrant Expression ◽  
Normal Individuals

Abstract Abstract 1114 Poster Board I-136 Background : It has been proposed that treating cancer cells with vectors that cause the over expression of MnSOD and catalase could inhibit tumor cell growth by disrupting the redox signaling involved with cell division as well as, therapeutically, by providing protection for normal cells. These results support the hypotheses that increasing the dismutation of mitochondrial superoxide alters redox signaling in cancer cells that can result in growth suppression. Peroxiredoxins (Prxs) are a ubiquitous family of multifunctional antioxidant thioredoxin-dependent peroxidases that have roles in the reversible inactivation of PTPs and PTEN in cells stimulated by growth factors and protect cells against oxidative stress and modulate intracellular signaling cascades (Rhee et al, Cell Biology 17:183-189, 2005). In our study, we investigated the changes of the levels of H2O2-removing enzymes (ie Prxs, glutathione peroxidase 1 (Gpx1), and catalase) on a single cell during IM therapy in newly diagnosed CML. Patients and Methods Six paired CML samples (two blast crisis, one accelerated phase, three chronic phases) were analyzed in a study was approved by the institutional review board. Patients gave written informed consent according to institutional guidelines. 400 mg or 600 mg of imatinib was given to the chronic phase and accelerated/blast crisis samples respectively. Following encircling cells from marrow BM aspiration from patients or normal individuals with the Dako Pen (Dako, Denmark) on a dry slides, cells were incubated with blocking solution (10% FBS in PBS) for 30minutes to block non-specific staining. Then, cells were incubated with specific primary antibodies to antioxidant enzymes in 0.2% TritonX-100/10% FBS/PBS solution overnight (1:100). After washing with PBS, cells were incubated with Alexa-488 or 594-conjugated goat antibodies to mouse or rabbit IgG, respectively for an hour. Confocal fluorescence images of cells were obtained with an LSM510 microscope (Carl Zeiss, Tornwood, NJ). Results Samples of newly diagnosed CML patients showed significantly decreased levels of Prx 2, but revealed increased level of catalase on single cell level. The immunohistochemical expression was well correlated with western blot results. As the level of Philadelphia chromosomes decreased with IM treatment, the expression levels of Prx II and catalase were restored to the levels of normal individuals. Using our technique, we are able to quantify the changes of Prx and catalase on each myeloid, erythroid and megakaryocytic lineages at the single cell level. Conclusions Decreased Prx 2 and elevated catalase levels at the time of diagnosis are closely correlated with the elevated bcr/abl kinase level in CML at the each single cell level. The aberrant expression of those antioxidant enzymes were back to the level of normal individuals after IM treatment. This method might be accurate and convenient to assess the changes of the level of Prx and Catalase especially in the situation of cytopenia with IM treatment. Understanding the molecular mechanisms of changes on antioxidant might be potent tools to develop more effective new drugs in CML patients especially for Imatinib resistant patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting the Oligomerization of BCR/ABL by Membrane Permeable Competitive Peptides Inhibits the Proliferation of Philadelphia Chromosome Positive Leukemic Cells

2011 ◽  
Vol 5 (1) ◽  
pp. 21-27
Author(s):  
Afsar Ali Mian ◽  
Marion Schull ◽  
Claudia Oancea ◽  
Yousef Najajreh ◽  
Jamal Mahajna ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Philadelphia Chromosome ◽  
Coiled Coil ◽  
Leukemic Cells ◽  
Abl Kinase ◽  
Transformation Potential ◽  
Targeted Inhibition ◽  
Peptide Transduction ◽  
Philadelphia Chromosome Positive

The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model. This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo.

Protective effects of soy-isoflavones in cardiovascular disease

2008 ◽  
Vol 28 (01/02) ◽  
pp. 85-88 ◽  
Author(s):  
D. Fuchs ◽  
H. Daniel ◽  
U. Wenzel
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Dietary Intervention ◽  
Mononuclear Cells ◽  
Oxidized Ldl ◽  
Proteome Analysis ◽  
Soy Isoflavones ◽  
Protective Effects ◽  
Estrogen Production

SummaryEpidemiological studies indicate that the consumption of soy-containing food may prevent or slow-down the development of cardiovascular disease. In endothelial cells application of a soy extract or a combination of the most abundant soy isoflavones genistein and daidzein both inhibited apoptosis, a driving force in atherosclerosis development, when applied in combination with oxidized LDL or homocysteine. Proteome analysis revealed that the stressorinduced alteration of protein expression profile was reversed by the soy extract or the genistein/daidzein mixture. Only few protein entities that could be functionally linked to mitochondrial dysfunction were regulated in common by both application forms of isoflavones. A dietary intervention with isoflavone-enriched soy extract in postmenopausal women, who generally show strongly increased cardiovascular risk due to diminished estrogen production, led to significant alterations in the steady state levels of proteins from mononuclear blood cells. The proteins identified by proteome analysis revealed that soy isoflavones may increase the anti-inflammatory response in blood mononuclear cells thereby contributing to the atherosclerosispreventive activities of a soy-rich diet. Conclusion: By proteome analysis protein targets were identified in vitro in endothelial cells that respond to soy isoflavones and that may decipher molecular mechanisms through which soy products exert their protective effects in the vasculature.

Plasma Level of IL-1β in Disseminated Intravascular Goagulation

1991 ◽  
Vol 65 (04) ◽  
pp. 364-368 ◽  
Author(s):  
Hideo Wada ◽  
Shigehisa Tamaki ◽  
Motoaki Tanigawa ◽  
Mikio Takagi ◽  
Yoshitaka Mori ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Plasma Level ◽  
Organ Failure ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Solid Cancer ◽  
Normal Individuals ◽  
The Relationship ◽  
Necrosis Factor

SummaryThe plasma level of interleukin-1β (IL-1β) was determined in normal individuals, patients with disseminated intravascular coagulation (DIC), patients in the pre-DIC period (within 7 days before the onset of DIC), and non-DIC patients to examine the relationship between DIC and the plasma ILlp level. The plasma IL-1β level was 0-0.085 ng/ml in normal individuals, with little difference being seen according to related age. It was significantly higher in the DIC group (0.19 ± 0.19 ng/ml) than in the pre-DIC group (0.05 ± 0.08 ng/ml) or the non-DIC group (0.09 ± 0.01 ng/ml). The plasma IL-1β level was not markedly elevated in leukemia patients, even in the DIC group, but it was significantly increased in the DIC group of solid cancer patients and was generally elevated in patients with sepsis. It was markedly elevated to 0.39 ± 0.26 ng/ml in patients with organ failure. When mononuclear cells were incubated with lipopolysaccharide, it was found that IL-1β, tumor necrosis factor, and tissue factor (TF) were released into the medium, and there was an increase of TF release from endothelial cells incubated with this medium. These results suggest that the increase in IL-Iβ reflected the activation of monocytes and may be an important factor in DIC and its associated organ failure.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

scholarly journals MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2108
Author(s):  
Manuela Tosi ◽  
Orietta Spinelli ◽  
Matteo Leoncin ◽  
Roberta Cavagna ◽  
Chiara Pavoni ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Current Treatment ◽  
New Drugs ◽  
Term Survival ◽  
Therapeutic Decisions ◽  
Key Factor ◽  
Combined Strategy

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

scholarly journals Identification of Circulating Gene Expression Signatures of Intracranial Aneurysm in Peripheral Blood Mononuclear Cells

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1092
Author(s):  
Vincent M. Tutino ◽  
Haley R. Zebraski ◽  
Hamidreza Rajabzadeh-Oghaz ◽  
Muhammad Waqas ◽  
James N. Jarvis ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Intracellular Signaling ◽  
Mononuclear Cells ◽  
Differential Expression Analysis ◽  
Validation Dataset ◽  
Cytokine Signaling ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Peripheral blood mononuclear cells (PBMCs) play an important role in the inflammation that accompanies intracranial aneurysm (IA) pathophysiology. We hypothesized that PBMCs have different transcriptional profiles in patients harboring IAs as compared to IA-free controls, which could be the basis for potential blood-based biomarkers for the disease. To test this, we isolated PBMC RNA from whole blood of 52 subjects (24 with IA, 28 without) and performed next-generation RNA sequencing to obtain their transcriptomes. In a randomly assigned discovery cohort of n = 39 patients, we performed differential expression analysis to define an IA-associated signature of 54 genes (q < 0.05 and an absolute fold-change ≥ 1.3). In the withheld validation dataset, these genes could delineate patients with IAs from controls, as the majority of them still had the same direction of expression difference. Bioinformatics analyses by gene ontology enrichment analysis and Ingenuity Pathway Analysis (IPA) demonstrated enrichment of structural regulation processes, intracellular signaling function, regulation of ion transport, and cell adhesion. IPA analysis showed that these processes were likely coordinated through NF-kB, cytokine signaling, growth factors, and TNF activity. Correlation analysis with aneurysm size and risk assessment metrics showed that 4/54 genes were associated with rupture risk. These findings highlight the potential to develop predictive biomarkers from PBMCs to identify patients harboring IAs.

scholarly journals A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jinguo Zhang ◽  
Wencai Guan ◽  
Xiaolin Xu ◽  
Fanchen Wang ◽  
Xin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Calcium Binding ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Progression ◽  
Bioinformatics Analyses ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
E Box

AbstractThe primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

scholarly journals Regulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and Cancers

2021 ◽  
Vol 22 (16) ◽  
pp. 8461
Author(s):  
Emanuela Chiarella ◽  
Annamaria Aloisio ◽  
Stefania Scicchitano ◽  
Heather Mandy Bond ◽  
Maria Mesuraca
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Transitional Cell ◽  
Biological Functions ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Novel Mirna ◽  
Mirna Expression Profiling ◽  
Mirna Deregulation

Powerful bioinformatics tools have provided a wealth of novel miRNA–transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.

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