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PubMed2004

Fibroblast growth factors in epithelial repair and cytoprotection.

Growth factors are polypeptides that stimulate the division of certain cell types at low concentrations. Fibroblast growth factor (FGF) 7 (FGF-7) and its homologue FGF-10 act specifically on various types of epithelial cells including keratinocytes of the skin, intestinal epithelial cells and hepatocytes. In addition, FGF-7 and FGF-10 have been shown to be more than growth factors: they can protect epithelial cells from damaging effects induced, for example, by radiation and oxidative stress. Therefore, they are currently in clinical trials for the treatment of oral mucositis, a severe side-effect of cancer therapy characterized by painful inflammation and ulceration of the oral epithelium. To gain insight into the mechanisms of FGF-7/FGF-10 action in epithelial cells, we searched for genes that are regulated by these growth factors. Indeed, we identified genes that help us to explain the mechanisms that underlie the effects of FGF-7. Most interestingly, several genes were identified that are likely to mediate the cytoprotective effect of FGF-7 for epithelial cells in vitro and possibly also in injured and diseased tissues in vivo.

Cell Division↗
PubMed2004

Cytoprotective effect of gallotannin in oxidatively stressed HaCaT keratinocytes: the role of poly(ADP-ribose) metabolism.

Oxidative stress-induced cytotoxicity is mediated in part by accelerated poly-ADP ribosylation. Peroxynitrite and hydrogen peroxide cause DNA breakage triggering the activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Overactivation of PARP-1 leads to cell dysfunction and cell death mainly due to depletion of NAD(+) (the substrate of PARP-1) and ATP. PARP-1 attaches most ADP-ribose residues onto itself, leading to downregulation of enzyme activity. Here, we have investigated the role of poly(ADP-ribose) glycohydrolase (PARG), the poly(ADP-ribose)-catabolyzing enzyme in oxidative stress-induced cytotoxicity in HaCaT cells. We have found that inhibition of PARG by gallotannin (GT) (50 microM) provided significant cytoprotection to peroxynitrite- or hydrogen peroxide-treated HaCaT cells, as assessed by lactate dehydrogenase release and propidium iodide uptake (parameters of necrotic cell death) as well as caspase activation (apoptotic parameter). GT pretreatment has also inhibited the depletion of cellular NAD(+) pools in hydrogen peroxide- or peroxynitrite-treated HaCaT cells. GT caused the accumulation of poly(ADP-ribose) and concomitant inhibition in cellular PARP activity in oxidatively stressed cells. Therefore, PARG is likely to contribute to maintaining the active state of PARP-1 by continuously removing inhibitory ADP-ribose residues from PARP-1.

Astringents↗
PubMed2006

Regulation of cutaneous drug-metabolizing enzymes and cytoprotective gene expression by topical drugs in human skin in vivo.

BACKGROUND: Individuality in the expression and regulation of hepatic drug-metabolizing enzymes (DMEs) and cytoprotective (CP) genes is an important determinant of treatment response. There is increasing evidence that many DMEs and CP genes are also expressed in human skin. Responses to topical drugs used to treat common skin diseases, such as psoriasis, are unpredictable and may potentially be rationalized, at least in part, by interindividual differences in cutaneous DME and CP gene expression. OBJECTIVES: We investigated whether three topical drugs [coal tar, all-trans retinoic acid (atRA) and clobetasol 17-propionate] used in routine clinical practice modulated the expression of a variety of DME and CP genes [cytochrome P450s, glutathione S-transferases (GSTs) and drug transporters] in healthy human skin in vivo. METHODS: Healthy adult volunteers (n = 30) were invited to participate in the study. Each subject was randomly allocated to receive two of the three study chemicals and one control site application. Crude coal tar (n = 13), atRA (n = 14) or clobetasol 17-propionate (n = 10) was applied under occlusion to photoprotected buttock skin for 96 h. A vehicle control (white soft paraffin) was also applied under the same conditions at an adjacent site in all subjects. Full-thickness punch biopsies (4-mm diameter) were then taken from treated and control sites. Total RNA was extracted and reverse transcribed into cDNA, which was used as a template in subsequent real-time polymerase chain reaction analysis, where fluorescent output was directly proportional to input cDNA concentration. Triplicate measurements of skin mRNA expression were made from each sample, and the arithmetic mean values taken. After logarithmic transformation, the paired t-test was used to compare values between treated and control skin. RESULTS: Cytochrome P450s CYP1A1, CYP1A2, CYP1B1, CYP2C18, quinone reductase (NQO-1), GSTP1, gamma-glutamyl cysteine synthetase (gamma-GCS), glutathione peroxidase-1 (GPx-1), cyclooxygenase-2 (COX-2) and haem oxygenase-1 (HO-1) were induced by coal tar; CYP26, NADPH P450 reductase (CPR), GSTP1 and HO-1 by atRA; and CYP3A5 by clobetasol 17-propionate. In contrast, CYP1A1 and CYP1A2 expression was suppressed by atRA, and gamma-GCS and MRP1 by clobetasol 17-propionate. Marked interindividual variation in gene regulation by topical drugs was seen for the majority of genes examined. CONCLUSIONS: These data demonstrate that topical drugs can modulate DME gene expression in human skin in vivo and indicate that variation in the expression and regulation of these genes may be a determinant of individuality in response to topical therapies for common skin diseases.

Administration, Cutaneous↗
PubMed2005

Glycine--an important neurotransmitter and cytoprotective agent.

BACKGROUND: Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and an anti-inflammatory, cytoprotective, and immune modulating substance. MATERIAL AND METHODS: Based on available literature, we discuss some of the important biological properties of glycine. In addition, we describe some clinical disorders where glycine plays a central role, either as an essential structural element, or through its metabolism or receptors. RESULTS: The past few years have witnessed a broadening of glycine research. The traditional prime interest in aspects related to its role as an inhibitory neurotransmitter in the central nervous system has been expanded to equally emphasize other organs and tissues. With the demonstration of glycine-gated chloride channels on neurons in the central nervous system, on most leukocytes, and subsequently on other cells as well, a unifying mechanism of action accounting for many of the widespread effects of glycine has been found. CONCLUSIONS: Glycine is a simple, easily available, and inexpensive substance with few and innocuous side-effects. The diversity of biological activities is well documented in the literature. Despite this, glycine has only gained a modest place in clinical medicine.

Cytoprotection↗
PubMed2005

The diurnal rhythm of the cytoprotective human trefoil protein TFF2 is reduced by factors associated with gastric mucosal damage: ageing, Helicobacter pylori infection, and sleep deprivation.

OBJECTIVES: To determine if the normal TFF2 diurnal rhythm is disrupted in those with increased risk of gastric morbidity. Trefoil proteins protect the gastrointestinal mucosa from damage and aid its repair. TFF2 is considered the major cytoprotective gastric trefoil protein. There is a marked circadian variation in gastric luminal TFF2 in young healthy volunteers with peak levels present during the night. METHODS: Gastric juice was aspirated at two hourly intervals over a 24-h period via a nasogastric tube. TFF2 was measured by quantitative western transfer analysis. Helicobacter pylori (H. pylori) status was measured by C13 urea breath test and by serology. The effects of H. pylori infection, sleep deprivation, and ageing, which cause increased gastric morbidity, on the TFF2 circadian rhythm were tested. RESULTS: H. pylori infection attenuated the increase in TFF2 that occurs during the night. The TFF2 diurnal rhythm was reduced in older people and both the TFF2 level reached and the time at which the maximum TFF2 concentration occurs were associated inversely with age (p < 0.005). Sleep deprivation delayed the normal night time increase in gastric TFF2 and resulted in an overall reduction in TFF2 secretion. CONCLUSIONS: H. pylori infection, ageing, and sleep deprivation cause a reduction in the TFF2 diurnal rhythm. The demonstration that the TFF2 rhythm is impaired in cohorts of individuals known to suffer gastric symptoms suggests that interventions to restore the normal TFF2 rhythm in those with poor mucosal protection could reduce morbidity.

Adolescent↗
PubMed2006

S-Nitrosylation of human variant albumin Liprizzi (R410C) confers potent antibacterial and cytoprotective properties.

The S-nitrosylated forms of certain proteins such as albumin have been thought to be circulating endogenous reservoirs of nitric oxide (NO) and may have potential as NO donors in therapeutic applications. In this study, we investigated the characteristics of R410C, a genetic variant of human serum albumin with two free thiols at positions 34 (Cys-34) and 410 (Cys-410), as a NO carrier via S-nitroso formation. A biotin switch assay revealed that Cys-410 was more rapidly and efficiently nitrosylated than was Cys-34. Nitrosylation of Cys-410 introduced only small conformational changes in the protein, which were detected by far-UV circular dichroism but not by near-UV circular dichroism. In addition, both native R410C and S-nitrosylated R410C did not induce molecular heterogeneity through oligomerization. S-Nitrosylated R410C exhibited strong antibacterial activity against Salmonella typhimurium in vitro and suppressed apoptosis of U937 human promonocytic cells induced by Fas ligand. In a rat ischemia-reperfusion liver injury model, S-nitrosylated R410C treatment significantly reduced liver damage, as indicated by markedly decreased release of liver enzymes (aspartate aminotransferase and alanine aminotransferase). Pharmacokinetic analyses indicated retention of the S-nitroso moiety of S-nitrosylated R410C in circulation after i.v. injection, with an approximate half-life of 20.4 min in the mouse. These data suggest that R410C can be a useful NO carrier and can be regarded as a new class of S-nitrosylated proteins possessing antibacterial and cytoprotective properties with a circulation time sufficient for in vivo biological activity.

Animals↗
PubMed2004

Protein adduct-trapping by hydrazinophthalazine drugs: mechanisms of cytoprotection against acrolein-mediated toxicity.

Acrolein is a highly toxic aldehyde involved in a number of diseases as well as drug-induced toxicities. Its pronounced toxicity reflects the readiness with which it forms adducts in proteins and DNA. As a bifunctional electrophile, initial reactions between acrolein and protein generate adducts containing an electrophilic center that can participate in secondary deleterious reactions (e.g., cross-linking). We hypothesize that inactivation of these reactive protein adducts with nucleophilic drugs may counteract acrolein toxicity. Because we previously observed that 1-hydrazinophthalazine (hydralazine) strongly diminishes the toxicity of the acrolein precursor allyl alcohol, we explored the possibility that hydralazine targets reactive acrolein adducts in proteins. We report that hydralazine abolished the immunoreactivity of an acrolein-modified model protein (bovine serum albumin), but only if the drug was added to the protein within 30 min of commencing modification by acrolein. The ability of a range of carbonyl-trapping drugs to interfere with "early" events in protein modification strongly correlated with their protective potencies against allyl alcohol toxicity in hepatocytes. In mass spectrometry studies using a model lysine-containing peptide, hydralazine rapidly formed hydrazones with Michael adducts generated by acrolein. Using an antibody raised against such ternary drug-acrolein-protein complexes in Western blotting experiments, clear adduct-trapping was evident in acrolein-preloaded hepatocytes exposed to cytoprotective concentrations of hydralazine ranging from 2 to 50 microM. These novel findings begin to reveal the molecular mechanisms whereby hydralazine functions as an efficient "protein adduct-trapping" drug.

Acrolein↗
PubMed2005

Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection.

In cerebral circulation, epileptic seizures associated with excessive release of the excitatory neurotransmitter glutamate cause endothelial injury. Heme oxygenase (HO), which metabolizes heme to a vasodilator, carbon monoxide (CO), and antioxidants, biliverdin/bilirubin, is highly expressed in cerebral microvessels as a constitutive isoform, HO-2, whereas the inducible form, HO-1, is not detectable. Using cerebral vascular endothelial cells from newborn pigs and HO-2-knockout mice, we addressed the hypotheses that 1) glutamate induces oxidative stress-related endothelial death by apoptosis, and 2) HO-1 and HO-2 are protective against glutamate cytotoxicity. In cerebral endothelial cells, glutamate (0.1-2.0 mM) increased formation of reactive oxygen species, including superoxide radicals, and induced major keystone events of apoptosis, such as NF-kappaB nuclear translocation, caspase-3 activation, DNA fragmentation, and cell detachment. Glutamate-induced apoptosis was greatly exacerbated in HO-2 gene-deleted murine cerebrovascular endothelial cells and in porcine cells with pharmacologically inhibited HO-2 activity. Glutamate toxicity was prevented by superoxide dismutase, suggesting apoptotic changes are oxidative stress related. When HO-1 was pharmacologically upregulated by cobalt protoporphyrin, apoptotic effects of glutamate in cerebral endothelial cells were completely prevented. Glutamate-induced reactive oxygen species production and apoptosis were blocked by a CO-releasing compound, CORM-A1 (50 microM), and by bilirubin (1 microM), consistent with the antioxidant and cytoprotective roles of the end products of HO activity. We conclude that both HO-1 and HO-2 have anti-apoptotic effects against oxidative stress-related glutamate toxicity in cerebral vascular endothelium. Although HO-1, when induced, provides powerful protection, HO-2 is an essential endogenous anti-apoptotic factor against glutamate toxicity in the cerebral vascular endothelium.

Animals↗
PubMed2006

Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation.

Accumulating evidence suggests that the simple and ubiquitous anion salt, nitrite (NO(2)(-)), is a physiological signaling molecule with potential roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection after ischemia-reperfusion. Human and animal studies of nitrite treatment and NO gas inhalation provide evidence that nitrite mediates many of the systemic therapeutic effects of NO gas inhalation, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction. With regard to nitrite-dependent hypoxic signaling, biochemical and physiological studies suggest that hemoglobin possesses an allosterically regulated nitrite reductase activity that reduces nitrite to NO along the physiological oxygen gradient, potentially contributing to hypoxic vasodilation. An expanded consideration of nitrite as a hypoxia-dependent intrinsic signaling molecule has opened up a new field of research and therapeutic opportunities for diseases associated with regional hypoxia and vasoconstriction.

Animals↗
PubMed2006

The cardenolide UNBS1450 is able to deactivate nuclear factor kappaB-mediated cytoprotective effects in human non-small cell lung cancer cells.

Non-small cell lung cancers (NSCLC) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and Vinca alkaloid derivatives, offers patients only slight clinical benefits. Part of the chemoresistance of NSCLCs results from the constitutive or anticancer drug-induced activation of the nuclear factor-kappaB (NF-kappaB) signaling pathways. The present study shows that human A549 NSCLC cells display highly activated cytoprotective NF-kappaB signaling pathways. UNBS1450, which is a cardenolide belonging to the same class of chemicals as ouabain and digitoxin, affected the expression and activation status of different constituents of the NF-kappaB pathways in these A549 tumor cells. The modifications brought about by UNBS1450 led to a decrease in both the DNA-binding capacity of the p65 subunit and the NF-kappaB transcriptional activity. Using the 3-(4,5-dimethylthiazol-2yl)-dephenyltetrazolium bromide colorimetric assay, we observed in vitro that UNBS1450 was as potent as taxol and SN38 (the active metabolite of irinotecan) in reducing the overall growth levels of the human A549 NSCLC cell line, and was more efficient than platin derivatives, including cisplatin, carboplatin, and oxaliplatin. The chronic in vivo i.p. and p.o. UNBS1450 treatments of human A549 orthotopic xenografts metastasizing to the brains and the livers of immunodeficient mice had a number of significant therapeutic effects on this very aggressive model.

Animals↗
PubMedDate not supplied

The cytoprotective effects of exogenous DNA fragments.

Ultraviolet irradiation of normal human keratinocytes induces a cytotoxic effect. The chromophore for this effect is believed to be genomic DNA. However, DNA damage is known to be repaired in UVB irradiated keratinocytes. The trigger for this DNA repair is potentially damaged DNA itself. To test the hypothesis that damaged DNA can induce the host cell's own DNA repair mechanism, we treated the keratinocytes with the damaged DNA and evaluated its cytoprotective effects. We have observed that fragmented calf thymus DNA irradiated and damaged with a UVC light can induce a protective effect in cultured human keratinocytes. Keratinocytes treated with UVC damaged DNA fragments are less susceptible to UVB irradiation-induced cell death as measured by neutral red uptake. Unirradiated exogenous DNA did not induce this protective effect. Similar protective effects can be seen with irradiated salmon sperm DNA. UVC damaged DNA fragments induced 60% increase in protection in human HaCaT keratinocyte in culture to the cell death induced by UVB. Similar protection was observed with UVC irradiated oligothymidylic acid (dT3-dT5) which increased the survival of human HaCaT keratinocytes after UVB irradiated by 50%. Isolated mononucleotides, irradiated or not, do not increase UVB survivability. Cellular DNA synthesis was greatly inhibited by UVB, becoming undetectable at 40 mJ/cm(2). Exogenous treatment with damaged fragments causes immediate and significant inhibition of total cellular DNA synthesis. This inhibition was dose dependent. Cells that undergo damage to their DNA are known to inhibit endogenous DNA synthesis via p53 suppressor gene activation. This is believed to allow them sufficient time to repair the host DNA. The cellular response to exogenous damaged DNA may be a similar mechanism.

Animals↗
PubMed2003

Cytoprotective effects of rebamipide and carteolol hydrochloride against ultraviolet B-induced corneal damage in mice.

PURPOSE: To analyze whether rebamipide (REB) and carteolol hydrochloride (CH) protect against UVB-induced corneal damage in mice. METHODS: BALB/c mice topically pretreated with REB (1 and 10 mM) or CH (1, 10, and 100 mM) were exposed to ultraviolet (UV) B light at 416 micro W/cm(2). To evaluate corneal damage, mire irregularity was graded, and the haze index was estimated by using digitized corneal images. The formation of oxidized DNA in the corneal epithelium resulting from UVB exposure was estimated by using quantitative immunohistochemistry for 8-hydroxy-2-deoxyguanosine (8OHdG index). To analyze the mechanism of cytoprotection by REB and CH against UVB-induced cell damage, the UV absorption spectrum in these agents was evaluated by spectrophotometry, and their hydroxyl radical scavenging effect was evaluated by the electron spin resonance (ESR) spin trapping technique with Fenton system hydroxy radical generation. RESULTS: Seventy-two hours after UVB exposure, the severity of mire irregularity, haze index, and 8OHdG index were significantly lower in mice pretreated with 10 mM (P < 0.05, P < 0.05, and P < 0.01, respectively) of REB and in mice pretreated with 10 mM (P < 0.05, P < 0.01, and P < 0.01, respectively) and 100 mM (P < 0.01, P < 0.01, and P < 0.01, respectively) of CH compared with mice treated with vehicle. The absorption spectrum of REB overlapped with the UVB wavelength, and that of CH overlapped partially. The ESR spin signal corresponding to the hydroxyl radical was reduced by the addition of REB or CH. CONCLUSIONS: REB and CH attenuate UVB-induced corneal damage, which may be partly responsible for their sunscreening and hydroxyl radical scavenging effects.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Cytoprotective effects of polyenoylphosphatidylcholine (PPC) on beta-cells during diabetic induction by streptozotocin.

Polyenoylphosphatidylcholine (PPC), a phosphatidylcholine-rich phospholipid extracted from soybean, has been reported to protect liver cells from alloxan-induced cytotoxicity. The present study aimed to investigate whether PPC protects pancreatic beta-cells from the cytotoxic injury induced by streptozotocin, thus preserving insulin synthesis and secretion. beta-Cells of the PPC-treated rats showed a significant reduction of cell death with lesser destruction of plasma membrane on streptozotocin insult. They demonstrated a rapid recovery of GLUT-2 expression, whereas almost irreversible depletion of membrane-bound GLUT-2 was seen in beta-cells of the rats treated with only streptozotocin. A similar cytoprotective effect of PPC was also monitored in the PPC-pretreated MIN6 cells. These beta-cells retained their ability to synthesize and secrete insulin and no alteration of glucose metabolism was detected. These results strongly suggest that PPC plays important roles not only in protecting beta-cells against cytotoxicity but also in maintaining their insulin synthesis and secretion for normal glucose homeostasis.

Animals↗
PubMed2004

Activated protein C variants with normal cytoprotective but reduced anticoagulant activity.

Recombinant activated protein C (APC), a well-defined anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC's less well-defined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys an increased risk of serious bleeding complications due to APC anticoagulant activity. To generate recombinant APC variants with reduced risk of bleeding due to reduced anticoagulant activity, we dissected APC's anticoagulant activity from its cytoprotective activity by site-directed mutagenesis. Using staurosporine-induced endothelial cell apoptosis assays, we show here that Ala mutations (RR229/230AA and KKK191_ 193AAA) in 2 APC surface loops that severely reduce anticoagulant activity result in 2 APC variants that retain normal antiapoptotic activity that requires protease activated receptor-1 and endothelial cell protein C receptor. Thus, it is possible to reduce anticoagulant activity while preserving antiapoptotic activity of recombinant APC variants. We suggest that therapeutic use of such APC variants may reduce serious bleeding risks while providing the beneficial effects of APC acting directly on cells.

Anticoagulants↗
PubMed2006

Integrative roles of transforming growth factor-alpha in the cytoprotection mechanisms of gastric mucosal injury.

BACKGROUND: Transforming growth factor alpha (TGFalpha) protects against gastric mucosal injury and facilitates wound healing. However, its overexpression is known to induce hypertrophic gastropathy resembling Menetrier's disease in transgenic (TG) mice on an FVB background, as one of the authors reported previously. We studied another TGFalpha-expressing mouse line on a CD1 background, whose gastric mucosa appears normal. Since this TG mouse had a strong resistance to ethanol-induced gastric injury, we considered the long-term effect of TGFalpha on several gastric protection mechanisms. METHODS: TGFalpha-expressing transgenic (TG) mouse lines bearing human TGFalpha cDNA under the control of the mouse metallothionein gene I promoter were generated on a CD1 mouse background, and analyzed their ethanol injury-resistant phenotypes produced by TGFalpha. RESULTS: In the TG mucosa, blood flow was well maintained after ethanol injury. Further, neural and inducible types of NO synthases were consistently and widely expressed in the TG mucosa, compared with the limited distribution of neural type NO synthase in the luminal pit region of the wild-type (WT) mucosa. COX-2 and its upstream transcription factor NfkB were constitutively elevated in the TG mucosa even before ethanol administration, whereas they were induced in the same region of the WT mucosa only after ethanol injury. Two anti-apoptotic proteins, HSP70 and Bcl-2, were upregulated in the TG mucosa even before ethanol administration, while they were not expressed in the WT mucosa before the injury. Furthermore, pro-caspase 3 activation was inhibited in the TG mucosa, while it was converted to the active form in the WT mucosa following ethanol administration. CONCLUSION: We conclude that TGFalpha maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.

Animals↗
PubMed2000

Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study.

Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75. 9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin's lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0. 04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

Adolescent↗
PubMed2006

Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts.

Chronic cholestatic liver diseases are characterized by impaired balance between proliferation and death of cholangiocytes, as well as vanishing of bile ducts and liver failure. Ursodeoxycholic acid (UDCA) is a bile acid widely used for the therapy of cholangiopathies. However, little is known of the cytoprotective effects of UDCA on cholangiocytes. Therefore, UDCA and its taurine conjugate tauroursodeoxycholic acid (TUDCA) were administered in vivo to rats simultaneously subjected to bile duct ligation and vagotomy, a model that induces cholestasis and loss of bile ducts by apoptosis of cholangiocytes. Because these two bile acids act through Ca2+ signaling, animals were also treated with BAPTA/AM (an intracellular Ca2+ chelator) or Gö6976 (a Ca2+-dependent protein kinase C-alpha inhibitor). The administration of UDCA or TUDCA prevented the induction of apoptosis and the loss of proliferative and functional responses observed in the bile duct ligation-vagotomized rats. These effects were neutralized by the simultaneous administration of BAPTA/AM or Gö6976. UDCA and TUDCA enhanced intracellular Ca2+ and IP3 levels, together with increased phosphorylation of protein kinase C-alpha. Parallel changes were observed regarding the activation of the MAPK and PI3K pathways, changes that were abolished by addition of BAPTA/AM or Gö6976. These studies provide information that may improve the response of cholangiopathies to medical therapy.

Animals↗
PubMed2006

Stat3 is required for cytoprotection of the respiratory epithelium during adenoviral infection.

The role of Stat3 in the maintenance of pulmonary homeostasis following adenoviral-mediated lung injury was assessed in vivo. Stat3 was selectively deleted from bronchiolar and alveolar epithelial cells in Stat3(DeltaDelta) mice. Although lung histology and function were unaltered by deletion of Stat3 in vivo, Stat3(DeltaDelta) mice were highly susceptible to lung injury caused by intratracheal administration of AV1-GFP, an early (E) region 1- and E3-deleted, nonproliferative adenovirus. Severe airspace enlargement, loss of alveolar septae, and sloughing of the bronchiolar epithelium were observed in Stat3(DeltaDelta) mice as early as 1 day after exposure to the virus. Although surfactant protein A, B, and C content and surfactant protein-B mRNA expression in Stat3(DeltaDelta) mice were similar, TUNEL staining and caspase-3 were increased in alveolar type II epithelial cells of Stat3(DeltaDelta) mice after exposure to virus. RNA microarray analysis of type II epithelial cells isolated from Stat3(DeltaDelta) mice demonstrated significant changes in expression of numerous genes, including those genes regulating apoptosis, supporting the concept that the susceptibility of Stat3-deficient mice to adenovirus was related to the role of Stat3 in the regulation of cell survival. AV1-Bcl-x(L), an E1- and E3-deleted, nonproliferative adenovirus expressing the antiapoptotic protein Bcl-x(L), protected Stat3(DeltaDelta) mice from adenoviral-induced lung injury. Adenoviral infection of the lungs of Stat3-deficient mice was associated with severe injury of the alveolar and bronchiolar epithelium. Thus, Stat3 plays a critical cytoprotective role that is required for epithelial cell survival and maintenance of alveolar structures during the early phases of pulmonary adenoviral infection.

Adenoviridae Infections↗