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PubMed1986

Dexamethasone effects on beta-adrenergic receptors and adenylate cyclase regulatory proteins Gs and Gi in ROS 17/2.8 cells.

Treatment of ROS 17/2.8 cells with dexamethasone (dex) increases (-)isoproterenol (ISO)-, PTH-, cholera toxin-, guanine nucleotide-, NaF-, and forskolin-stimulated adenylate cyclase activity. Enhanced hormone stimulation was first apparent 12 h after dex addition. (-)-[3H]Dihydroalprenolol binding, displaceable by ISO, increased up to 2-fold in dex-treated cells. This effect depended on protein synthesis and closely paralleled the extent and time course of the increase in adenylate cyclase stimulation. In dex-treated cells there was also an increase in the maximum velocity of guanyl-5'-yl imidodiphosphate-stimulated adenylate cyclase, a decrease in the lag time for guanyl-5'-yl imidodiphosphate enzyme activation in the presence of ISO from 3 to 1 min, increased stimulation of adenylate cyclase by cholera toxin, and increased labeling of 47,000 and 42,000 mol wt proteins by [32P]NAD in the presence of cholera toxin. [32P]NAD ribosylation in the presence of pertussis toxin resulted in the labeling of 40,000 mol wt protein, which was also increased by 20-50% in dex-treated cells. However, pertussis toxin treatment did not augment or reduce the effect on hormone stimulation, although it increased the cAMP response to PTH and (-)ISO. These findings suggest that dex increases (-)ISO stimulation of adenylate cyclase in ROS 17/2.8 cells by jointly increasing the number of hormone receptors and the abundance of Gs, the guanine nucleotide binding regulatory protein.

Adenosine Diphosphate Ribose↗

PubMed1988

Effects of retinoic acid on alkaline phosphatase messenger ribonucleic acid, catecholamine receptors, and G proteins in ROS 17/2.8 cells.

Retinoic acid (RA) inhibits the increases in alkaline phosphatase (AP) and hormone-stimulated adenylate cyclase that accompany the growth of ROS 17/2.8 osteosarcoma cells in culture. The RA effects were first detected 2 days after initiation of treatment and were dose dependent, with an EC50 of 100 nM. The reduction in the hormone-responsive adenylate cyclase activity was associated with lower levels of beta-catecholamine receptors, without a change in apparent receptor affinity and with lower levels of the GTP-binding proteins Gs and Gi, visualized by NAD-dependent [32P]ADP ribosylation. The reduction in AP was correlated with a decrease in the steady state level of AP mRNA. RA had no effect on cell proliferation or saturation density. Retinoids thus inhibit the same features that are promoted by glucocorticoids in ROS 17/2.8 cells. These features seem to be subject to coordinate regulation, probably at the pretranslational level.

Adenylyl Cyclases↗

PubMed1989

1,25-Dihydroxyvitamin D3 inhibits transcription of type I collagen genes in the rat osteosarcoma cell line ROS 17/2.8.

Our previous studies have demonstrated that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3)] reduces type I collagen synthesis and steady state levels of procollagen mRNA in cultured fetal rat calvaria and rat osteosarcoma cells. To determine whether 1,25-(OH)2D3 regulates transcription of type I collagen genes, transcription rates were measured directly in nuclei isolated from ROS 17/2.8 cells using a nuclear run-off assay. Transcription was allowed to proceed in the presence of [32P]UTP for 20 min, at which time incorporation of radiolabeled UTP into trichloroacetic acid-precipitable material was maximal. UTP incorporation was inhibited 90% by 3 micrograms/ml actinomycin-D and 40% by 1 microgram/ml alpha-amanitin. Treatment of ROS 17/2.8 cells with 1,25-(OH)2D3 inhibited procollagen gene transcription in a concentration and time dependent manner. Procollagen transcription was reduced by approximately 50% of the control rate by 10 nM 1,25-(OH)2D3, and this inhibition was maximal after 24 h of 1,25-(OH)2D3 treatment. The inhibition of procollagen transcription was specific for collagen, since total RNA synthesis and beta-actin transcription were not inhibited by 1,25-(OH)2D3. The magnitude of the decrease of procollagen transcription by 1,25-(OH)2D3 was comparable to its inhibition of steady state procollagen mRNA levels, suggesting that transcription is the predominant mechanism by which 1,25-(OH)2D3 regulates collagen gene expression in bone cells.

Animals↗

PubMed1991

Desensitization of rat osteoblast-like cells (ROS 17/2.8) to parathyroid hormone uncouples the adenosine 3',5'-monophosphate and cytosolic ionized calcium response limbs.

We have investigated the effects of PTH-induced desensitization on second messenger interactions in the rat osteosarcoma cell line ROS 17/2.8. Adenylate cyclase activation was assessed by accumulation of immunoassayable cAMP, and cytosolic calcium ion ([Ca2+]i) concentrations were measured in adherent perifused cells loaded with the Ca2(+)-sensitive bioluminescent protein aequorin. Preexposure to rat PTH-(1-34) [rPTH-(1-34); 10(-8) M for 48 h, then 10(-7) M for 24 h] dramatically reduced (by 85%) the cAMP response to fresh challenge [2 min; 10(-9)-10(-7) M rPTH-(1-34)], but the peak PTH-induced rise of [Ca2+]i was not diminished significantly (0-20%). Nevertheless, we did observe other changes in the PTH-induced [Ca2+]i response. Exposure of treated cells to (Bu)2cAMP nearly abolished the [Ca2+]i response to PTH (greater than 80% reduction), but had much less effect on the PTH-stimulated [Ca2+]i increment of the naive cells (less than 35% reduction). Treated cells also had a blunted [Ca2+]i response to PTH in the presence of low extracellular calcium (greater than 60% reduction), but in the naive cells, low extracellular Ca2+ did not significantly diminish the peak PTH-induced [Ca2+]i rise, although low extracellular Ca2+ dramatically reduced the area under this [Ca2+]i transient (greater than 50%). Low extracellular Ca2+ had no influence on the peak [Ca2+]i responses of treated cells to bradykinin or prostaglandin F2 alpha. Although the peak PTH-stimulated [Ca2+]i rise of treated cells in normal Ca2+ medium was not significantly attenuated, the time to half-maximum [Ca2+]i concentration was significantly increased (greater than 100%), and the area under the [Ca2+]i transient was diminished. These alterations in the [Ca2+]i response of treated cells were not observed upon challenge with bradykinin or prostaglandin F2 alpha. Thus, 1) the cAMP and [Ca2+]i responses of ROS 17/2.8 cells to rPTH-(1-34) are not obligatorily coupled; 2) the response of naive cells to PTH includes both the release of Ca2+ from intracellular stores and the entry of extracellular Ca2+; and 3) pretreatment of these cells with rPTH-(1-34) augments the dependence on Ca2+ entry during hormone rechallenge. We propose that the preserved PTH-stimulated [Ca2+]i rise in treated cells results partly from loss of cAMP-mediated inhibition of extracellular Ca2+ entry.

Animals↗

PubMed1991

Parathyroid hormone (PTH)-induced intracellular Ca2+ signalling in naive and PTH-desensitized osteoblast-like cells (ROS 17/2.8): pharmacological characterization and evidence for synchronous oscillation of intracellular Ca2+.

We showed recently that the initial peak cytosolic ionized calcium ([Ca2+]i) response to PTH (2-min exposure) is preserved relative to the cAMP response in osteoblast-like rat osteosarcoma cells (ROS 17/2.8) desensitized by 72-h exposure to PTH. We attempted in the present studies to determine the mechanisms for preservation of the [Ca2+]i response and to explore the effects of longer PTH rechallenges. The [Ca2+]i response to a 20-min perifusion with rat PTH [rPTH-(1-34)] was monitored by aequorin luminescence in both naive and PTH-desensitized ROS 17/2.8 cells. The responses of both naive and desensitized cells consisted of two phases: an initial peak, followed by an intermediate plateau that was sustained in the presence of PTH. We observed in the naive cell populations synchronous oscillations in [Ca2+]i concentration during this second phase (amplitude, 10-60 nM; frequency, 1-3/100 sec). These oscillations were maintained through extracellular calcium (EC Ca2+) entry; the initial peak was the result of Ca2+ release from intracellular stores. In desensitized cells, these two phases could not be clearly separated with respect to Ca2+ source, but, as we showed before, exhibited an enhanced dependence on EC Ca2+ entry for the response to PTH. Nevertheless, in the desensitized cells, the sustained [Ca2+]i response was diminished in magnitude and showed little oscillatory behavior. Brief exposure to neomycin sulfate, an inhibitor of phosphoinositide turnover, attenuated the PTH-induced [Ca2+]i rise in both naive and desensitized cells. Protein kinase-C activity did not appear to be required for either phase of the PTH-induced [Ca2+]i response. Exposure to cholera toxin attenuated the [Ca2+]i response to hormone in both naive and desensitized cells, more markedly in the latter. Cholera toxin treatment dramatically increased basal cAMP levels in both cell preparations; PTH-stimulated cAMP production was unchanged in naive cells, but increased nearly 4-fold in desensitized cells. We propose that the preserved PTH-induced peak [Ca2+]i rise in desensitized cells results primarily from the diminished regulation of EC Ca2+ entry by the cAMP response limb. The attenuated sustained oscillatory behavior observed in desensitized cells upon rechallenge with hormone may be the result of reduced phosphoinositide turnover and reduced Ca2+-stimulated Ca2+ release. Thus, the [Ca2+]i response to PTH in osteoblast-like cells is complex and modulable and seems to provide a number of ways to regulate intracellular metabolism under various conditions. We speculate that this plasticity of the [Ca2+]i response to PTH is related to the pleiotropic actions of the hormone on cells of the osteoblast lineage.

Animals↗

PubMed1996

Serum stimulation of parathyroid hormone-related peptide gene expression in ROS 17/2.8 osteosarcoma cells through transcriptional and posttranscriptional mechanisms.

The gene encoding PTH-related peptide (PTHrP), a protein that plays a primary role in the development of humoral hypercalcemia of malignancy, is widely expressed in normal and neoplastic tissues. This study demonstrates that expression of the PTHrP gene has features of early response genes, including up-regulation after serum repletion of serum-starved ROS 17/2.8 (rat osteosarcoma) cells. The PTHrP messenger RNA (mRNA) levels were induced within 30 min and peaked at 4 h. Elevated mRNA levels were accompanied by an increase in secreted PTHrP. The serum effects on PTHrP mRNA levels were blocked by actinomycin D, suggesting a requirement for gene transcription. Nuclear run-on assays revealed a 3-fold increase in PTHrP gene transcription 4 h after exposure to serum. Deletions of the 5' flanking sequence of the rat PTHrP gene fused to the chloramphenicol acetyltransferase gene and transfected into ROS 17/2.8 cells showed that the serum-responsive region is located between -1.05 kb and -0.3 kb upstream of the transcription start site. PTHrP mRNA levels were also induced by cycloheximide, another feature common to early response genes. The PTHrP mRNA half-life in serum-starved cells was 56 min. Serum treatment prolonged the half-life 2.7-fold, suggesting serum-induced stabilization of the mRNA. Insulin and epidermal growth factor also induced PTHrP mRNA expression in a time-dependent manner analogous to serum, indicating that the effects of serum may be mediated, at least partially, through these agents. In summary, serum up-regulated PTHrP mRNA expression through both transcriptional and posttranscriptional mechanisms. This rapid stimulation by growth factors suggests that PTHrP may contribute to the early cellular response after growth factor stimulation.

Animals↗

PubMed1991

Vitamin D receptor phosphorylation in transfected ROS 17/2.8 cells is localized to the N-terminal region of the hormone-binding domain.

The human 1,25-dihydroxyvitamin D3 receptor (hVDR) has been recently shown to be phosphorylated in vitro by casein kinase-II. Most of the residues phosphorylated by this enzyme were shown to reside between Asn160 and Asp232, a region near the N-terminal boundary of the hormone-binding domain. We report here that the hVDR is also phosphorylated in vivo after transfection into ROS 17/2.8 cells. In addition to testing full-length hVDR, we analyzed several internally deleted hVDR mutants. The expression and phosphorylation of full-length and mutated hVDRs were monitored in transfected cells by metabolic labeling with either [35S]methionine or [32P]orthophosphate, followed by immunopurification using monoclonal anti-VDR antibody linked to agarose beads. Transfected hVDR is distinguishable from the endogenous rat VDR when the immunoprecipitated proteins are resolved on sodium dodecyl sulfate-polyacrylamide gels. Significant phosphorylation of transfected full-length hVDR was observed in ROS 17/2.8 cells, and it was less dependent on the presence of 1,25-dihydroxyvitamin D3 than that of the endogenous rat receptor. Most importantly, the region of in vivo phosphorylation, as defined by internal deletion mutants, resides between Met197 and Val234. Therefore, we have localized the major site of phosphorylation of hVDR to residues in the N-terminal region of the hormone-binding domain. The boundaries of this region fall within the amino acid segment defined for phosphorylation of hVDR by casein kinase-II in vitro, suggesting that VDR is an in vivo substrate for casein kinase-II or a related protein kinase.

Amino Acid Sequence↗

PubMed1999

Effect of ionizing radiation on the differentiation of ROS 17/2.8 osteoblasts through free radicals.

Although the acceleration of bone regeneration by radiation has been reported, the mechanisms of action of radiation on bone are unclear. The present results indicate that ionizing radiation-stimulated differentiation could result from the generation of reactive oxygen species during radiation exposure. The free radical release is considered as the most important mechanism of bone effect by radiation treatment. In addition, we report that radiation induced transient activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation and the transcription factor, AP-1. The JNK and AP-1 activation is mediated with radiation-released free radicals in ROS 17/2.8 osteoblasts. These results indicate that ionizing radiation at a single dose of up to 5 Gray stimulates differentiation of ROS 17/2.8 osteoblasts via free radial release which may affect JNK/SAPK and AP-1 activities.

Animals↗

PubMed2000

Role of activator protein 1 transcriptional activity in the regulation of gene expression by transforming growth factor beta1 and bone morphogenetic protein 2 in ROS 17/2.8 osteoblast-like cells.

In osteoblastic cells, transforming growth factor beta1 (TGF-beta1) has been found to regulate the expression of a variety of proto-oncogenes including c-fos, c-jun, and junB. The c-fos in particular has been implicated in the mitogenic effect of TGF-beta1. Here, we examined the role of these early response genes in the regulation of osteoblast (OB) gene expression by two members of the TGF-beta superfamily, TGF-beta1 and bone morphogenetic protein 2 (BMP-2). In ROS 17/2.8 cells, TGF-beta1 as well as BMP-2 up-regulated the expression of junB and c-fos messenger RNAs (mRNAs), and this increase was correlated in both cases with an increase in activator protein 1 (AP-1) DNA-binding activity involving JunB and c-Fos proteins. Protein kinase C (PKC)- and protein tyrosine kinase (PTK)-dependent pathways have been implicated in both TGF-beta1 signaling and AP-1 gene regulation. Therefore, using the kinase inhibitors chelerythrine chloride and genistein, we showed that PKC and PTK activities, respectively, participated in TGF-beta1- and BMP-2-induced increases in junB mRNA levels. Similarly, these kinase activities were involved in the stimulatory effect of BMP-2 on c-fos mRNA expression. Using a natural dominant negative for AP-1 transcriptional activity in ROS 17/2.8 cells, we then showed that AP-1 transcription factors mediated TGF-beta1- and BMP-2-regulated expression of the (alpha1) collagen I gene as well as TGF-beta1-regulated expression of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor. Our data emphasize the role of the AP-1 transcription factor in TGF-beta1 and BMP-2 signaling and highlight the importance of this transcription factor family in the expression of OB genes.

Animals↗

PubMed2000

Regulation of PTH/PTH-related protein receptor expression by endogenous PTH-related protein in the rat osteosarcoma cell line ROS 17/2.8.

We have utilized clonal lines of the rat osteoblastic cell line ROS 17/2.8 stably transfected with full-length parathyroid hormone-related protein (PTHrP) cDNA in a sense or an antisense orientation to examine the effects of alteration in the production of endogenous PTHrP on expression of the PTH/PTHrP receptor. In the stably transfected clonal cell lines, changes in PTH/PTHrP receptor expression were evaluated by Northern blot analysis, whole-cell ligand binding of 125I-[Tyr36] PTHrP (1-36), and exogenous PTHrP (1-34)-stimulated cyclic adenosine monophosphate (cAMP) accumulation. Compared to control (vector-transfected) cells, PTHP-overproducing (sense-transfected) cells exhibited a marked decrease in the expression of PTH/PTHrP receptor mRNA and PTHrP ligand binding, as well as a corresponding decrease in the PTHrP (1-34)-stimulated cAMP response. By contrast, the antisense-transfected cells showed a marked increase in expression of PTH/PTHrP receptor mRNA and PTHrP (1-34) ligand binding, but a significant increase in the PTHrP (1-34)-stimulated cAMP response was not detected. Using antisense-transfected ROS cells, PTH/PTHrP receptor mRNA expression and 125I-[Tyr36] PTHrP (1-36) binding were downregulated by treatment for 24 h with exogenous PTHrP (1-36), forskolin, or dibutyryl cAMP. The findings extend those of earlier studies showing receptor downregulation by exogenous PTH by indicating that endogenous PTHrP, as well as circulating PTH, may help regulate receptor production; and suggesting that even very low concentrations of the peptide may influence receptor production.

Animals↗

PubMed2001

Reactive oxygen species (ROS)-generating oxidases in the normal rabbit cornea and their involvement in the corneal damage evoked by UVB rays.

The corneas of albino rabbits were irradiated (5 min exposure once a day) with UVB rays (312 nm) for 4 days (shorter procedure) or 8 days (longer procedure). The eyes were examined microbiologically and only the corneas of sterile eyes or eyes with non-pathogenic microbes were employed. Histochemically, the activities of reactive oxygen species (ROS)-generating oxidases (xanthine oxidase, D-amino acid oxidase and alpha-hydroxy acid oxidase) were examined in cryostat sections of the whole corneas. Biochemically, the activity of xanthine oxidoreductase/xanthine oxidase was investigated in the scraped corneal epithelium. UVB rays significantly changed enzyme activities in the corneas. In comparison to the normal cornea, where of ROS-generating oxidases only xanthine oxidase showed significant activity in the corneal epithelium and endothelium, D-amino acid oxidase was very low and alpha-hydroxy acid oxidase could not be detected at all, in the cornea repeatedly irradiated with UVB rays, increased activities of xanthine oxidase and D-amino acid oxidase were observed in all corneal layers. Only after the longer procedure the xanthine oxidase and D-amino acid oxidase activities were decreased in the thinned epithelium in parallel with its morphological disturbances. Further results show that the xanthine oxidase/xanthine oxidoreductase ratio increased in the epithelium together with the repeated irradiation with UVB rays. This might suggest that xanthine dehydrogenase is converted to xanthine oxidase. However, in comparison to the normal corneal epithelium, the total amount of xanthine oxidoredutase was decreased in the irradiated epithelium. It is presumed that xanthine oxidoreductase might be released extracellularly (into tears) or the enzyme molecules were denatured due to UVB rays (particulary after the longer procedure). Comparative histochemical and biochemical findings suggest that reactive oxygen species-generating oxidases (xanthine oxidase, D-amino acid oxidase) contribute to the corneal damage evoked by UVB rays.

Alcohol Oxidoreductases↗

PubMed2006

The NF-kappaB-mediated control of ROS and JNK signaling.

NF-kappaB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kappaB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemoresistance in cancer. With regard to TNFalpha, the NF-kappaB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45beta/Myd118. Notably, NF-kappaB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFalpha, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kappaB. The antioxidant activity of NF-kappaB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC)--a component of Ferritin, the primary iron-storage protein complex found in cells--and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kappaB controls proapoptotic JNK signaling triggered by TNFalpha. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kappaB, including some cancers and chronic inflammatory conditions.

Animals↗

PubMed2003

Negative transcriptional regulation of connexin 43 by Tbx2 in rat immature coronal sutures and ROS 17/2.8 cells in culture.

BACKGROUND: Tbx2 is a member of the T-box family of transcriptional regulatory genes with an extensive but not yet fully understood role in embryonic development. This study explores the potential role of Tbx2 in calvarial morphogenesis. OBJECTIVES: To explore the hypothesis that Tbx2 has a negative regulatory effect on the expression of connexin 43 (Cx43), a protein necessary for cell-to-cell communication; document the presence of Tbx2 protein in the developing cranial sutures; and determine the spatial pattern of expression of this developmentally regulated transcription factor in calvariae. DESIGN: The osteoblast-like cell line ROS 17/2.8 was stably transfected with sense or antisense Tbx2. Immunohistochemistry and Western blotting was used to study Tbx2 and Cx43 expression in these cells and sections of embedded developing coronal sutures. RESULTS: The ROS 17/2.8 cells transfected with antisense Tbx2 showed a decrease in expression of Tbx2 protein and an increase in expression of endogenous Cx43. The reverse is seen with sense-transfected cells. Both of these proteins are expressed in rat developing coronal sutures. The pattern of Tbx2 expression in the developing was also reciprocal to the pattern of Cx43 expression. Tbx2 protein is concentrated in the center of the sutural blastema, an area devoid of Cx43 protein localization. Conversely, Tbx2 protein expression is low in the periphery of the sutures, in which there is high Cx43 protein expression. CONCLUSIONS: Taken together, these studies suggest that Tbx2 protein is a negative regulator of Cx43 expression at the transcriptional level in cranial sutures in vivo.

Animals↗

PubMed2005

Black tea protects thymocytes in tumor-bearing animals by differential regulation of intracellular ROS in tumor cells and thymocytes.

The accumulated in vitro evidence indicates that many tumors induce T-cell apoptosis as a mechanism of inhibiting antitumor activity. This downregulation of cell-mediated immune functions occurring at the late stages of the disease may be causally related to the thymic involution, because the thymus is the major site of T-cell maturation, extensive proliferation, and differentiation. Our results showed that in Erhlich's ascites carcinoma cell (EAC)-bearing mice, the number of EAC was inversely proportional to the thymocyte count in the host's thymus, which is the primary immune organ. Further studies indicated the presence of tumor-induced thymocyte apoptosis in EAC bearers. Black tea prolonged the survival of the tumor bearer by successfully restricting tumor progression as well as protecting the thymus from tumor insult. In fact, black tea inhibited thymic apoptosis while inducing programmed cell death of EAC. Interestingly, the tea regulated the oxidant status differentially in EAC and thymocytes--i.e., it reduced the EAC-induced reactive oxygen species (ROS) generation in the thymus while activating the same in the EAC. A similar effect of black tea was obtained when thymocytes were cultured in the presence of cell-free ascitic fluid, thereby indicating that black tea could directly reduce oxidative stress, an activity independent of its tumoricidal property. As a result, the maturation block in thymocyte subpopulations in tumor bearers was ameliorated significantly in black tea-treated animals. Our results demonstrate that black tea protects thymocytes in the tumor bearer by regulating the intracellular ROS in tumor cells and thymocytes differentially, thereby strengthening its candidacy in future anticancer therapeutic regimens.

Animals↗

PubMed2003

Proteinuria and vascular changes after renal irradiation: the role of reactive oxygen species (ROS) and vascular endothelial growth factor (Vegf).

Proteinuria occurs in all degrees of radiation nephropathy and can be present without other symptoms. In this study, radiation-induced proteinuria in C3H mice demonstrated a clear dose-response relationship and was apparent before the onset of significant structural vascular changes and decreases in renal function. This suggests that proteinuria is not a secondary event due to loss of the vascular structure. In an attempt to ameliorate radiation-induced proteinuria and progressive renal failure, two factors were studied. The influence of reactive oxygen species (ROS), which are generated by infiltrating neutrophils and mediate proteinuria in models of acute glomerular injury, was the first to be investigated. Short-term administration of the reactive oxygen scavengers superoxide dismutase (SOD) and catalase did not reverse an established radiation-induced proteinuria. Continuous administration of the antioxidant N-acetylcysteine (NAC) also failed to inhibit this proteinuria. However, since no direct assessment of the impact of these interventions on renal redox status was made, the putative role of ROS in radiation-induced proteinuria and nephropathy remains undefined. The second factor studied was vascular endothelial growth factor (Vegf), which is suggested to be involved in glomerular vessel permeability and the development of proteinuria in some models of renal disease. Northern blot analysis of mRNA from whole kidneys did not demonstrate any increased expression of Vegf after irradiation. There was also no change in the ratio of the different Vegf isoforms (PCR analysis), either in the whole kidney or in isolated glomeruli. No significant role for Vegf was identified for radiation-induced vascular changes or proteinuria, although post-transcriptional changes cannot be excluded.

Angiogenesis Inducing Agents↗

PubMed2006

Induction of apoptosis via the modulation of reactive oxygen species (ROS) production in the treatment of myeloid leukemia.

Recent advances in genetic and molecular biology have provided greater insight into the biology of acute myeloid leukemia (AML). These investigations have shown that AML is a heterogeneous disease of biologically different entities. Current therapeutic approaches to AML are based on chemotherapy, but the side effects of the drugs used and various complications, including infections and bleeding, are sometimes fatal. In addition, responses to therapy and long-term outcome differ depending on the subentity in question. Therefore, it is essential to develop new therapeutic strategies such as biology adapted treatment based on the individual molecular pathogenesis of AML. Natural compounds appear to be safer than the current chemotherapeutic drugs, and we have therefore sought new potential agents among various natural compounds with the ability to induce the apoptosis of myeloid leukemic cells. Recently, we found that a highly toxic reactive oxygen species (ROS) generated via the hydrogen peroxide/myeloperoxidase [H(2)O(2)/MPO/halide] system by natural compounds induces apoptosis in MPO-positive leukemic cells. This result is of great interest in establishing novel therapeutic approaches to AML mediated through ROS-induced apoptosis of leukemic cells.

Antineoplastic Agents↗

PubMed2004

ROS effects on neurodegeneration in Alzheimer's disease and related disorders: on environmental stresses of ionizing radiation.

Neurodegenerative processes associated with Alzheimer's disease are complex and involve many CNS tissue types, structures and biochemical processes. Factors believed involved in these processes are generation of Reactive Oxygen Species (ROS), associated inflammatory responses, and the bio-molecular and genetic damage they produce. Since oxidative processes are essential to energy production, and to other biological functions, such as cell signaling, the process is not one of risk exposure, as for cigarettes and cancer, but one where normal physiological processes operate out of normal ranges and without adequate control. Thus, it is necessary to study the ambiphilicity that allows the same molecule (e.g., beta amyloid) to behave in contradictory ways depending upon the physiological microenvironment. To determine ways to study this in human populations we review evidence on the effects of an exogenous generator of ROS, ionizing radiation, in major population events with radionuclides (e.g., Hiroshima and Nagasaki; Chernobyl Reactor accident; environmental contamination in Chelyabinsk (South Urals) where plutonium was produced, and in the nuclear weapons test area in Semipalatinsk, Kazakhstan). The age evolution, and traits, of neurodegenerative processes in human populations in these areas, may help us understand how IR affects the CNS. After reviewing human population evidence, we propose a model of neurodegeneration based upon the complexity of CNS functions.

Alzheimer Disease↗

PubMed2006

Facing up the ROS labyrinth--Where to go?

Evidence indicates that oxidative stress refers to a condition where cells are subjected to excessive levels of reactive oxygen species (ROS). Overall vascular function is dependent upon a fine balance between oxidant and antioxidant mechanisms which is required, at least in part, for proper functioning of the endothelium. Considerable experimental and clinical data indicate that the intracellular oxidant milieu is also involved in several redox-sensitive cellular signaling pathways, such as ion transport systems, protein phosphorylation, and gene expression and thus also plays important roles as modulator of vascular cell function, such as cell growth, apoptosis, migration, angiogenesis and cell adhesion. Overproduction of ROS under pathophysiologic conditions is integral in the development of vascular disease. This fact stimulated an intensive search of new pharmacological approaches to improve vascular hemeostasis and, particularly those intended to decrease oxidative stress or augment the antioxidant defense mechanisms.

Adrenergic beta-Antagonists↗