Periostin in vitreoretinal diseases

Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with α-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-β2 (TGF-β2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases.     

Comparison of the effects of concanavalin A on cell growth and the transport of 3-O-methylglucose in chick embryo fibroblasts

The proliferative capacity of Chick embryo fibroblasts was modified by Con A treatment. Con A decreased the growth of fibroblasts from young embryos (8 days), whereas the lectin stimulated the growth of fibroblasts from older embryos (16 days). This differential effect of Con A did not result from changes in cellular permeability to thymidine, but rather from Con A induced modifications of hexose transport. Changes in hexose transport would cause, as a response, parallel modifications in glycolysis and hence energy charge, which would alter proliferative capacity.     

Side effects of Ricinus lectin (RCA 120) on nucleic acid synthesis in chick embryo fibroblasts

When fibroblasts from chick embryos were treated with Ricinus lectin, the effects observed depended on the stage of development of the embryo from which the cells were prepared. Thus, in 16-day fibroblasts, which have a weak proliferative capacity, nucleic acid synthesis was less sensitive to the effect of this lectin than that in 8-day fibroblasts, whose proliferative capacity is high.     

Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease

Cardiomyocytes proliferate profusely during early development and for a brief period after birth in mammals. Within a month after birth, this proliferative capability is dramatically reduced in mammals unlike lower vertebrates where it persists into adult life. The zebrafish, for example, retains the ability to regenerate the apex of the heart following resection by a mechanism predominantly driven by cardiomyocyte proliferation. Differences in proliferative capacity of cardiomyocytes in adulthood between mammals and lower vertebrates are closely liked to ontogenetic or phylogenetic factors. Elucidation of these factors has the potential to provide enormous benefits if they lead to the development of therapeutic strategies that facilitate cardiomyocyte proliferation. In this review, we highlight the differences between Mammalian and Zebrafish cardiomyocytes, which could explain at least in part the different proliferative capacities in these two species. We discuss the advantages of the zebrafish as a model of cardiomyocyte proliferation, particularly at the embryonic stage. We also identify a number of key molecular pathways with potential to reveal key steps in switching cardiomyocytes from a quiescent to a proliferative phenotype.     

Stimulation of peripheral guinea pig blood lymphocytes by autologous epidermal cells]

Using a strictly autologous (and not syngeneic) mixed culture system in the guinea-pig, it was shown that Mitomycin C treated ear epidermal cells (E) were capable of stimulating peripheral blood lymphocytes (L) from the same animal. The proliferative response of the lymphocytes as measured by 3H thymidine incorporation, is optimal on the 5th day of culture, and when the ratio of the concentrations of the two cell populations (L : E) is 1 : 1. The autoreactivity of the lymphocytes varies with the animal.     

Protein kinase C-dependent NF-κB activation is altered in T cells by chronic stress

Chronic stress has been associated with impaired immune function. In this work we studied the effect of chronic mild stress (CMS) exposure on the early intracellular pathways involved in T cells after stimulation with mitogen. We found that mitogen stimulation of T lymphocytes from CMS-exposed mice resulted in a reduction of the intracellular [Ca²⁺] rise, an impairment of growth-promoting protein kinase C (PKC) activation, a lower NF-κB activation and an increase in the inhibitory cAMP-protein kinase A (PKA) pathway activity with respect to those found in control lymphocytes. However, T cell activation with the direct PKC activator phorbol 12-myristate 13-acetate plus calcium ionophore led to a similar proliferative response in both CMS and control lymphocytes, indicating that signals downstream of PKC would not be affected by stress. In summary, our results show that chronic stress induced an alteration in T cell early transduction signals that result in an impairment of the proliferative response.Received 11 February 2005; received after revision 20 May 2005; accepted 6 June 2005     

Angiopathie rétinienne provoquée par l'imino-dipropionitrile chez le rat

Summary Imino-dipropionitrile (IDPN) brings on to the rat an angiopathy which, when the animals are treated with cortisone, presents a great morphologic ressemblance with diabetic retinopathy.     

Quantitation of proliferative mucosal cells of the Mongolian gerbil on a weight basis

Summary Quantitation of proliferative activity of the intestine of the gerbil shows a substantial decrease in proliferative activity as compared to the mouse. The use of dry vs wet weights proved to have no bearing on calculations of proliferative activity. The gerbil may prove a useful model for drug and radiation experimentation.This work was supported by National Science Foundation grant No. GB35522. Reprint requests should be addressed to: H.S., Health Physics, Merck Sharp & Dohme Research Laboratories, West Point (Pennsylvania 19486, USA).     

Examination of the fundus of the eye of renal hypertensive dogs

Summary Only 1 of 7 dogs with long-standing renovascular hypertension showed clear changes in the fundus. No distinct retinopathy was seen in the others. Ophthalmoscopy alone is thus of limited value in assessing the progress of benign hypertension in the dog.     

Determination of proliferative compartments in human tumors

Summary Extracorporeal normothermic perfusion with radioactive thymidine allows a cytological, histological and structural analysis of proliferative compartments of human kidney carcinomas in whole-tumor autoradiograms.Supported by a grant from Bundesministerium für Jugend, Familie und Gesundheit, Bonn.     

Secretogranin III: a diabetic retinopathy-selective angiogenic factor

Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen-induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as “selective angiogenesis blockers” for targeted therapy.     

Progesterone regulation of implantation-related genes: new insights into the role of oestrogen

Genomic profiling was performed on explants of late proliferative phase human endometrium after 24-h treatment with progesterone (P) or oestradiol and progesterone (17β-E₂+P) and on explants of menstrual phase endometrium treated with 17β-E₂+P. Gene expression was validated with real-time PCR in the samples used for the arrays, in endometrium collected from early and mid-secretory phase endometrium, and in additional experiments performed on new samples collected in the menstrual and late proliferative phase. The results show that late proliferative phase human endometrium is more responsive to progestins than menstrual phase endometrium, that the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P in vitro, and that genes that are fully dependent on the continuous presence of 17β-E₂ during P exposure can be distinguished from those that are P-dependent to a lesser extent. Therefore, 17β-E₂ selectively primes implantation-related genes for the effects of P. H. Dassen, C. Punyadeera: These authors contributed equally. Received 18 December 2006; received after revision 6 February 2007; accepted 8 March 2007     

Senescence suppressors: their practical importance in replicative lifespan extension in stem cells

Recent animal and clinical studies report promising results for the therapeutic utilization of stem cells in regenerative medicine. Mesenchymal stem cells (MSCs), with their pluripotent nature, have advantages over embryonic stem cells in terms of their availability and feasibility. However, their proliferative activity is destined to slow by replicative senescence, and the limited proliferative potential of MSCs not only hinders the preparation of sufficient cells for in vivo application, but also draws a limitation on their potential for differentiation. This calls for the development of safe and efficient means to increase the proliferative as well as differentiation potential of MSCs. Recent advances have led to a better understanding of the underlying mechanisms and significance of cellular senescence, facilitating ways to manipulate the replicative lifespan of a variety of primary cells, including MSCs. This paper introduces a class of proteins that function as senescence suppressors. Like tumor suppressors, these proteins are lost in senescence, while their forced expression delays the onset of senescence. Moreover, treatments that increase the expression or the activity of senescence suppressors, therefore, cause expansion of the replicative and differentiation potential of MSCs. The nature of the activities and putative underlying mechanisms of the senescence suppressors will be discussed to facilitate their evaluation.     

Patterns of neuroglial proliferation in spinal cord white matter following exposure to ionizing radiation

Summary X-irradiation temporarily decreases the proliferative activity of neuroglia in immature rat spinal cord. Later, the proliferative activity in these irradiated regions surpasses that noted in control rats. Areas adjacent to the irradiated region have a greater than normal percentage of labelled neuroglia and may also be a source for neuroglia which re-populate the irradiated zone.Acknowledgments. Sincere thanks to Ms Jane Leiting for her assistance in doing the cell counts and to Mr Napoleon Phillips for preparing the autoradiographs. Supported by USPHS grant NS 04761.     

Modification of mixed lymphocyte reactivity between DLA-identical dog sibs, after in vivo sensitization

Mixed lymphocyte reactions (MLR) with cells from DLA-identical dog sibs are nonresponsive either in primary or in secondary interactions after in vitro priming. However, lymphocytes from animals sensitized in vivo against DLA-identical sibs can show increased proliferative response to their immunizing donor. The kinetics of this reaction are similar to MLR across the DLA-barrier, although its intensity is less important. This proliferation may reflect minor histocompatibility antigenic differences.     

The role of repair in radiobiology

Apart from cancer and mutation induction, radiobiological effects on mammals are mostly attributable to cell 'death', defined as loss of proliferative capacity. Survival curves relate retention of that capacity to radiation dose, and often manifest a quasi-threshold ('shoulder'). The shoulder is attributable to an initial mechanism of repair ('Q-repair') which is gradually depleted as dose increases. Another form of repair, which is not depleted ('P-repair'), increases the dose required to deliver an average of one lethal event per cell (dose 'D0'). Neither form of repair can unambiguously be linked with repair of defects in isolated DNA. An important initial lesion may well be disruption of the complex structural relationship between the DNA, nuclear membrane and associated proteins. One form of P-repair may be restoration of that structural relationship.     

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats

The effect of canavanine treatment on the electroretinograms of healthy and streptozotocin-diabetic rats was studied. The characteristic amplitudes of the a-wave, W₂ and W₃ oscillatory potentials were markedly diminished in the 2-week streptozotocin-diabetic rats compared with those of the control rats. In contrast, the amplitudes of all the responses of the canavanine-pretreated streptozotocin-diabetic rats were practically indistinguishable from those of the control animals. Our results prompt further investigations for the use of amino acid analogues and other inducers of molecular chaperones in easing the chronic consequences of diabetes such as retinopathy. Received 3 June 1998; received after revision 14 August 1998; accepted 14 August 1998     

大鼠侧脑室下区神经干细胞具有不易兴奋性

目的建立体外培养大鼠侧脑室下区神经干细胞的方法,观察大鼠侧脑室下区神经干细胞的膜兴奋性。方法无血清培养方法体外分离、纯化孕15～16dwistar胎鼠的侧脑室下区神经干细胞,用免疫荧光鉴定干细胞标记蛋白nestin表达情况、用tuj-1和GFAP免疫染色研究体外NSC的分化情况;取第二代神经干细胞给予DiBACA（3）染色后,经高浓度氯化钾刺激,激光共聚焦显微镜动态扫描,观察侧脑室神经干细胞的兴奋性。结果采用无血清培养基体外分离的神经干细胞具有自我增殖、多向分化潜能等干细胞一般特点,且表达干细胞的标记蛋白nestin;采用DiBAC4（3）染色,高浓度钾刺激后,细胞荧光强度无显著变化,即细胞膜电位无明显改变,神经干细胞具有不易兴奋性。结论采用无血清培养方法成功分离扩增大鼠脑内神经干细胞;由大鼠侧脑室分离而来的神经干细胞具有不易兴奋性。     

Polychlorinated biphenyl-induced modification of lymphocyte response to plant mitogens in rats

Summary In PCB-treated rats total white cell and differential counts and lymphocyte proliferative response to PWM were unaltered. The lymphocyte response to PHA was increased in treated animals.Acknowledgements. Supported by grants from the Medical Research Council of Canada. We thank the Monsanto Chemical Co., St. Louis, Mo., for donating Aroclor 1254 and Dr.P. Cano for the protein determinations and electrophoresis.     

Proliferation status defines functional properties of endothelial cells

Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell–cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi’s sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells.