Cobblestone-Area Forming Cells Derived from Patients with Mantle Cell Lymphoma Are Enriched for CD133+ Tumor-Initiating Cells

Mantle cell lymphoma (MCL) is associated with a significant risk of therapeutic failure and disease relapse, but the biological origin of relapse is poorly understood. Here, we prospectively identify subpopulations of primary MCL cells with different biologic and immunophenotypic features. Using a simple culture system, we demonstrate that a subset of primary MCL cells co-cultured with either primary human mesenchymal stromal cells (hMSC) or murine MS-5 cells form in cobblestone-areas consisting of cells with a primitive immunophenotype (CD19−CD133+) containing the chromosomal translocation t (11;14)(q13;q32) characteristic of MCL. Limiting dilution serial transplantation experiments utilizing immunodeficient mice revealed that primary MCL engraftment was only observed when either unsorted or CD19−CD133+ cells were utilized. No engraftment was seen using the CD19+CD133− subpopulation. Our results establish that primary CD19−CD133+ MCL cells are a functionally distinct subpopulation of primary MCL cells enriched for MCL-initiating activity in immunodeficient mice. This rare subpopulation of MCL-initiating cells may play an important role in the pathogenesis of MCL.     

Glutathione S-transferase M1 and T1 genotypes and myocardial infarction

Myocardial infarction (MI), which is the most important manifestation of coronary artery disease, is the leading cause of morbidity and mortality in the world. Glutathione S transferases (GSTs) are enzymes responsible for the metabolism of numerous xenobiotics and are known to be polymorphic in humans. We investigated the association between the GSTM1 and GSTT1 gene polymorphisms and MI. The study consists of 296 healthy controls and 324 consecutive patients who had undergone coronary angiography for suspicion of coronary artery disease and with a past history of myocardial infarction. DNA was extracted from whole blood of patient and control. GSTM1 and GSTT1 gene polymorphisms were examined using multiplex PCR. We found that the null GSTM1 was associated with protective effect on MI, although this increase was not significant for GSTM1 (p < 0.054). However, GSTT1 genotype was associated with an increase in the risk of developing MI. In addition to after adjusting other all coronary risk factors, the interactive effect of GSTT1 null genotype remained statistically significant (p < 0.001) for MI disease but GSTM1 null genotype was not statistically significant. Patients, who smoke having the null genotypes of GSTM1, were at a higher risk for developing MI (p < 0.001, OR = 0.41, 95 % CI = 0.240–0.207). There was an effect of interaction of GSTM1 null genotype and smoking on MI development between patient and control groups (p < 0.001). Our results showed that individuals with the null genotypes for GSTM1 had protective effect, while GSTT1 was at a higher risk for MI disease. In addition, there was additional effects of smoking when smoking and non-smoking groups were compared.     

Poly(ADP-ribose) glycohydrolase and poly(ADP-ribose)-interacting protein Hrp38 regulate pattern formation during Drosophila eye development

Drosophila Hrp38, a homolog of human hnRNP A1, has been shown to regulate splicing, but its function can be modified by poly(ADP-ribosyl)ation. Notwithstanding such findings, our understanding of the roles of poly(ADP-ribosyl)ated Hrp38 on development is limited. Here, we have demonstrated that Hrp38 is essential for fly eye development based on a rough-eye phenotype with disorganized ommatidia observed in adult escapers of the hrp38 mutant. We also observed that poly(ADP-ribose) glycohydrolase (Parg) loss-of-function, which caused increased Hrp38 poly(ADP-ribosyl)ation, also resulted in the rough-eye phenotype with disrupted ommatidial lattice and reduced number of photoreceptor cells. In addition, ectopic expression of DE-cadherin, which is required for retinal morphogenesis, fully rescued the rough-eye phenotype of the hrp38 mutant. Similarly, Parg mutant eye clones had decreased expression level of DE-cadherin with orientation defects, which is reminiscent of DE-cadherin mutant eye phenotype. Therefore, our results suggest that Hrp38 poly(ADP-ribosyl)ation controls eye pattern formation via regulation of DE-cadherin expression, a finding which has implications for understanding the pathogenic mechanisms of Hrp38-related Fragile X syndrome and PARP1-related retinal degeneration diseases.     

The effects of Fusilade (Fluazifop-<Emphasis Type="Italic">p</Emphasis>-butyl) on germination,mitotic frequency and α-amylase activity of lentil (<Emphasis Type="Italic">Lens culinaris</Emphasis> Medik.) seeds

In this study, seed germination percentages, effects on phases of mitosis and α-amylase enzyme activity of lentil seeds treated with four different concentrations (0.25, 0.5, 1 and 1.5%) of Fusilade (Fluazifop-p-butyl) were determined. Median EC (effective concentration) values were calculated according to seed germination percentages after treatment for 72 h. Germination percentages of primary lentil roots decreased with increasing Fusilade concentrations. Cytological observations showed that the mitotic frequency in root meristematic cells were decreased parallel to the increase in concentrations and all Fusilade concentrations applied decreased the activity of α-amylase enzyme in lentil seeds. The obtained results indicate that the herbicide Fusilade had the ability to cause reduction in seed germination, mitotic frequency and also α-amylase activity of lentil seeds.     

Intracerebroventricular serotonin reduces the degree of acute hypoxic ventilatory depression in peripherally chemodenervated rabbits

Hypoxia causes changes in the rate of synthesis or release of neurotransmitters in the brain. The accumulation of serotonin (5-HT) in the central nervous system might cause hypoxic respiratory depression. In the present study, we aimed to examine the role of central 5-HT on normoxic and acute hypoxic ventilatory depression (AHVD) in peripheral chemoreceptors denervated rabbits. All experiments were performed in peripherally chemodenervated rabbits anesthetized with intravenous injection of urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). For intracerebroventricular (ICV) administration of 5-HT (20 microg/kg) and ketanserin (10 microg/kg), a cannula was placed in left lateral ventricle by stereotaxic method. Respiratory frequency (fR), tidal volume (VT), ventilation minute volume (VE) and systemic arterial bood pressure (BP) were recorded in each experimental phases and mean arterial pressure was calculated (MAP). Heart rate (HR) was also determined from the pulsation of BP. The effects of ICV serotonin and ICV ketanserin on the indicated parameters during air breathing (normoxia) and breathing of hypoxia (8% O2--92% N2) were investigated. During hypoxia, fR, VT, VE, MAP and HR decreased, and AHVD was thus obtained. ICV injection of 5-HT during normoxia caused significant increases in VT (P < 0.001) and in VE (P < 0.01). On the other hand, ICV 5-HT injection reduced the degree of AHVD in peripherally chemodenervated rabbits during hypoxia (fR; P < 0.05, VT; P < 0.05 and VE; P < 0.01). After ICV injection of ketanserin, the enhancement of 5-HT on VE was prevented during normoxia. On the breathing of hypoxic gas after ICV ketanserin, the degree of AHVD was augmented. In conclusion, our findings suggested that central 5-HT increases normoxic ventilation and reduces the degree of AHVD during hypoxia and that ICV ketanserin prevents the stimulatory effect of 5-HT on respiration and augments AHVD.     

The nucleosome-remodeling ATPase ISWI is regulated by poly-ADP-ribosylation

ATP-dependent nucleosome-remodeling enzymes and covalent modifiers of chromatin set the functional state of chromatin. However, how these enzymatic activities are coordinated in the nucleus is largely unknown. We found that the evolutionary conserved nucleosome-remodeling ATPase ISWI and the poly-ADP-ribose polymerase PARP genetically interact. We present evidence showing that ISWI is target of poly-ADP-ribosylation. Poly-ADP-ribosylation counteracts ISWI function in vitro and in vivo. Our work suggests that ISWI is a physiological target of PARP and that poly-ADP-ribosylation can be a new, important post-translational modification regulating the activity of ATP-dependent nucleosome remodelers.     

Design of a bactericidal hydrogel scaffold containing genipin crosslinked HF-18 peptide

Wound healing is a process getting affected by internal and external factors and might be interrupted by infections. To overcome infections during wound healing, novel antibacterial agents such as antimicrobial peptides have gained popularity because of the rising antibiotic resistance. Therefore, in this study, a three-dimensional polymeric scaffold was designed for the controlled release of HF-18 peptide, with the contribution of hyaluronic acid, chondroitin sulfate, and chitosan polymers with the crosslinker genipin. The obtained scaffold structure (OPT) was found to have interconnected pores, was pH-responsive and swelled more in acidic conditions (5446.5% at pH: 5.0). It was observed that HF-18-loaded OPT (P-OPT) was able to release HF-18 peptide both in acidic and neutral conditions in a controlled release manner. This study also demonstrated that both OPT and P-OPT were biocompatible and promoted L929 cell attachment and migration. Antimicrobial activity assessments demonstrated that P-OPT was effectively bactericidal on Staphylococcus aureus and methicillin-resistant S. aureus. Moreover, OPT produced a synergistic effect on the antimicrobial activity of HF-18 peptide, as P-OPT showed activity below the reported MIC value. As a result, OPT is considered a promising scaffold as a carrier for HF-18 for wound healing.     

Control of Oxidative Damage in Rheumatoid Arthritis By Gold(I)-Thiolate Drugs

The roles of anti-arthritic gold(I)-thiolate drugs such as disodium aurothiomalate ('Myocrisin') in the modulation or promotion of oxygen radical-mediated oxidative damage in vivo ate reviewed. In particular, the precise molecular mechanisms by which these novel second-line agents exert their therapeutic effects are discussed in terms of (i) the direct and indirect control of enzymes involved in the generation or scavenging of reactive oxygen speices (ROS) such as superoxide ion, hydrogen peroxide and hydroxyl radical, (ii) the protection of proteins and relevant enzyme systems against attack by ROS and (iii) their direct involvement in the production (at appropriate 'target' sites) or scavenging of ROS in vivo. In addition, the role of the orally-effective gold(I)-phosphine complex auranofin in the control of oxidative damage in rheumatoid arthritis is also discussed.