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PubMed2002

Atrial natriuretic peptide reduces cyclosporin toxicity in renal cells: role of cGMP and heme oxygenase-1.

Using cultured proximal renal tubular epithelial cells (LLC-PK1), the present study investigates the effect of atrial natriuretic peptide (ANP) on cytotoxicity induced by cyclosporin A (CsA). Preincubation with ANP (1-100 nM) protected LLC-PK1 cells from CsA-induced toxicity in a concentration-dependent manner. A cytoprotective effect comparable to ANP was observed when preincubating the cells with 8-bromo cGMP (1-100 microM) or the antioxidant heme oxygenase (HO) metabolite bilirubin (0.1-10 microM). ANP or cGMP produced increases in HO-1 protein levels at concentrations that were also effective in cellular protection. Moreover, incubation with ANP or 8-bromo cGMP led to increased HO activity, i.e., formation of bilirubin in the cell lysate (up to 3-fold over basal). Tin protoporphyrin-IX (SnPP; 19 microM), an inhibitor of HO activity, completely abolished ANP-induced cytoprotection. Our results demonstrate that HO-1 is a cellular target of ANP and cGMP in renal cells. HO-1 induction and ensuing formation of antioxidant metabolites may be a novel pathway by which ANP protects from CsA-dependent nephrotoxicity and preserves renal function.

Animals↗
PubMed2003

Catechin attenuates 6-hydroxydopamine (6-OHDA)-induced cell death in primary cultures of mesencephalic cells.

Past studies have shown the protective effects of tea catechins on oxidative cell damage induced by 6-OHDA in PC12 cells. In this study we verified whether or not catechin prevents 6-OHDA-induced oxidative cell damage in primary cultures of rat mesencephalic cells. On exposure to 6-OHDA (200 microM), the cultures showed a marked decrease in cell viability, disturbances in lipid peroxidation, and an increased generation of NO, as assayed by MTT, TBARS and nitrite assays, respectively. Introduction of catechin significantly attenuated the cell death caused by 6-OHDA at concentrations of 3.4, 34 and 340 microM in a dose-related manner. Catechin produced no marked changes on 6-OHDA-induced increases in NO, but caused a significant inhibition of lipid peroxidation. These results suggest that catechins offer similar cytoprotection against 6-OHDA-induced oxidative cell damage in mesencephalic cell cultures, as previously described in PC12 cells. The cytoprotective function of catechin results from its antioxidant property and is not due to the inhibition of nitric oxide synthase. These findings further support and substantiate traditional consumption of catechin rich green/black tea as protection against neurodegenerative diseases like Parkinsonism.

Animals↗
PubMed2005

Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldehyde scavenger histidyl-containing analogues of carnosine.

The synthesis, scavenging activity, and cytoprotective profiles of histidyl-containing carnosine analogues bearing hydrazide or 1,2-diol moieties is reported. Some compounds have demonstrated higher aldehyde-sequestering efficiency than carnosine and were also efficient in protecting SH-SY5Y neuroblastoma cells and rat hippocampal neurons from 4-hydroxy-trans-2,3-nonenal (HNE)-mediated death. The cytoprotective efficacy of these compounds suggests their potential use as therapeutic agents for disorders that involve excessive membrane lipids peroxidation and HNE-mediated neuronal toxicity.

Aldehydes↗
PubMed2004

Prevention of Fas-mediated hepatic failure by transferrin.

Recent studies in lymphohemopoietic cells show that transferrin (Tf), a pivotal component of iron transport and metabolism, also exerts cytoprotective functions. We show here in a murine model that Tf interferes with Fas-mediated hepatocyte death and liver failure. The mechanism involves the downregulation of apoptosis via BID, cytochrome c, caspase-3 and caspase-9, and upregulation of antiapoptotic signals via Bcl-xL. The results obtained with iron-saturated Tf, Apo-Tf and the iron-chelator salicylaldehyde isonicotinoyl hydrazone indicate that the observed antiapoptotic effect of Tf was not mediated by iron alone. In conclusion, the data suggest that Tf has broader functions than previously recognized and may serve as a cytoprotective agent.

Animals↗
PubMed2006

Reactive oxygen species and their detoxification in healing skin wounds.

Injury to the skin initiates a cascade of events, which finally lead to at least partial reconstruction of the wounded tissue. The wound-healing process has been well described at the histological level, but the underlying molecular mechanisms are still poorly defined. To gain insight into these mechanisms we searched for genes, which are regulated by skin injury. Interestingly, some of the genes that we identified encode cytoprotective proteins, in particular enzymes, which detoxify reactive oxygen species (ROS). Since ROS are produced in high amounts at the wound site as a defense against invading bacteria, the expression of these genes is most likely important for the protection of cells against these toxic molecules. In this review, we summarize the results on the expression of cytoprotective genes in wounded skin, and we discuss their possible roles in the wound-healing process.

Animals↗
PubMed2006

Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions.

Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.

Adult↗
PubMed2002

Nitric oxide increases adrenomedullin receptor function in rat mesangial cells.

BACKGROUND: Adrenomedullin (ADM) exerts antiproliferative effects on rat mesangial cells in vitro and, therefore is a possible renoprotective agent. In contrast, nitric oxide (NO) is capable of exerting both cytoprotective and cytotoxic actions. It was the objective of the present study to examine whether NO stimulates the ADM system. METHODS: Rat mesangial cells were incubated with the NO donors GSNO and SNAP, the guanylate cyclase inhibitor ODQ, and the cGMP analog 8-bromo-cGMP. ADM radioligand binding, ADM-induced intracellular cAMP-accumulation (radioimmunoassay) and ADM receptor gene expression (TaqMan real time PCR) were measured. RESULTS: Twenty-four hour treatment of mesangial cells with GSNO and SNAP (100 micromol/L each) increased the maximal binding of ADM to its receptor from 52%+/- 4% to 101%+/- 4% (P < 0.001) and 81%+/- 2% (P < 0.001), respectively. GSNO, SNAP (both 100 micromol/L) and 8-bromo-cGMP (50 micromol/L) increased EC50 from 9.9 x 10-8 to 7.0 x 10-10, 4.8 x 10-10, 1.1 x 10-9, respectively. In contrast, combined pretreatment with GSNO (100 micromol/L) and ODQ (100 micromol/L) reduced EC50 to values similar to the control cells (2.4 x 10-8). In contrast, ADM receptor gene expression was reduced significantly by different concentrations of GSNO, SNAP, and by 50 micromol/L 8-bromo-cGMP, but not by 8-bromo-cAMP. CONCLUSIONS: NO increases ADM signal transduction via a cGMP dependent pathway. This effect is caused, at least in part, by an increase in ADM receptor availability and is counteracted in a feedback manner on the mRNA level. This mechanism might direct the impact of NO on mesangial cell function toward cytoprotection.

Animals↗
PubMed2003

Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) reduces ischemia and/or reperfusion damage in several organs, but the mechanisms involved are largely unknown. We used freshly isolated rat hepatocytes to investigate the mechanisms by which ANP enhances hepatocyte resistance to hypoxia. The addition of ANP (1 micromol/L) reduced the killing of hypoxic hepatocytes by interfering with intracellular Na(+) accumulation without ameliorating adenosine triphosphate (ATP) depletion and pH decrease caused by hypoxia. The effects of ANP were mimicked by 8-bromo-guanosine 3', 5'-cyclic monophosphate (cGMP) and were associated with the activation of cGMP-dependent kinase (cGK), suggesting the involvement of guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A/B ANP receptors. However, stimulating NPR-C receptor with des-(Gln(18), Ser(19),Gly(20),Leu(21),Gly(22))-ANP fragment 4-23 amide (C-ANP) also increased hepatocyte tolerance to hypoxia. C-ANP protection did not involve cGK activation but was instead linked to the stimulation of protein kinase C (PKC)-delta through G(i) protein- and phospholipase C-mediated signals. PKC-delta activation was also observed in hepatocytes receiving ANP. The inhibition of phospholipase C or PKC by U73122 and chelerythrine, respectively, significantly reduced ANP cytoprotection, indicating that ANP interaction with NPR-C receptors also contributed to cytoprotection. In ANP-treated hepatocytes, the stimulation of both cGK and PKC-delta was coupled with dual phosphorylation of p38 mitogen-activated protein kinase (MAPK). The p38 MAPK inhibitor SB203580 abolished ANP protection by reverting p38 MAPK-mediated regulation of Na(+) influx by the Na(+)/H(+) exchanger. In conclusion, ANP recruits 2 independent signal pathways, one mediated by cGMP and cGK and the other associated with G(i) proteins, phospholipase C, and PKC-delta. Both cGK and PKC-delta further transduce ANP signals to p38 MAPK that, by maintaining Na(+) homeostasis, are responsible for ANP protection against hypoxic injury.

Animals↗
PubMed2002

A phase III randomized evaluation of amifostine in stage IIIA/IIIB non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensification: preliminary findings.

Despite the progress in pharmaceutical therapeutics and the hardware and software advances supporting radiation oncology, the major advance in the treatment of locally advanced nonmetastatic non-small cell lung cancer during the previous decade has been the adoption of integrated combined-modality therapy. This has resulted in an appreciation of the associated increase in treatment-related morbidity that has fostered new efforts to maximize the therapeutic index, including evaluation of cytoprotective agents. This report presents the preliminary data from a prospective randomized phase III trial of radiation therapy (64.8 Gy) administered concurrently with paclitaxel and carboplatin with posterior consolidation with cisplatin and gemcitabine with or without amifostine. The data to date do not support a cytoprotective advantage to the use of intravenous amifostine targeting esophagitis at 200 mg/m2/d before radiation. Further efforts to assess the role and potential of amifostine in the treatment of patients with non-small cell lung cancer are recommended.

Adult↗
PubMed2001

Geranylgeranylacetone promotes induction and secretion of thioredoxin in gastric mucosal cells and peripheral blood lymphocytes.

Thioredoxin (TRX) is a redox-active protein which is induced by oxidative stresses and shows a variety of biological activities including cytoprotection against oxidative stress. We recently reported that geranylgeranylacetone (GGA), an anti-ulcer drug, induces TRX in rat hepatocytes. In this study, we demonstrate that GGA promotes induction and secretion of TRX in rat gastric mucosal cells and human peripheral blood lymphocytes (PBLs). Western blotting and a sensitive sandwich ELISA showed that TRX was induced by GGA in the cell lysates and culture supernatants of rat gastric mucosal RGM-1 cells and human PBLs. LDH releasing assay showed that GGA protected rat gastric mucosal RGM-1 cells from ethanol-induced cytotoxicity. Moreover, exogenous recombinant wild type TRX decreased 51Cr release from primary cultured rat gastric mucosal cells incubated with ethanol or hydrogen peroxide in a dose-dependent manner, whereas recombinant mutant TRX (C32S/C35S), in which the two cysteines were replaced with serines in its active site, did not. These results indicate that GGA promotes the induction and secretion of TRX in a variety of types of cells and suggest that induced or secreted TRX may play an important role in the cytoprotective action of GGA on gastric mucosal cells.

Animals↗
PubMed2004

Cold-storage affects antioxidant properties of apples in Caco-2 cells.

Data on the composition of phenolic antioxidant compounds present in food plants and assessment of their activity are essential for epidemiological explanation of the health benefits of fruit and vegetables. Various factors such as cultivation methods, industrial processing, and storage may affect the final concentrations of phytochemicals in food plants and their eventual bioactivity. This study investigated the influence of commercial cold-storage periods on the antioxidant properties of apples grown either by organic or integrated systems. In both cases, total phenolics and total antioxidant activity decreased only in the first 3 mo and only in apples with skin (P < 0.05), suggesting that cold storage rapidly impoverishes these properties in skin but not in pulp. Assessment of antioxidant bioactivity in vitro, measured in terms of intracellular antioxidant, cytoprotective, and antiproliferative activity in human colon carcinoma (Caco-2) cells (differentiated to normal intestinal epithelia for intracellular antioxidant and cytoprotective effects), showed strong, time-related decreases over 6 mo of cold storage for all 3 parameters (P < 0.01), irrespective of the cultivation system. These findings with integrated and organic apples further support the concept that organic systems of cultivation do not generally provide real health benefits. Moreover, the data from the present study clearly show that factors such as cold storage may affect the antioxidant properties of apples. Epidemiological studies on the cancer-preventive benefits of fruits and vegetables should take into account the cold-storage bias for apples, and possibly for other products.

Antioxidants↗
PubMed2001

Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death.

Purines such as adenosine, inosine, and hypoxanthine are known to have potent antiinflammatory effects. These effects generally are believed to be mediated by cell surface adenosine receptors. Here we provide evidence that purines protect against oxidant-induced cell injury by inhibiting the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins such as histones and PARP itself. Overactivation of PARP depletes cellular NAD+ and ATP stores and causes necrotic cell death. We have identified some purines (hypoxanthine, inosine, and adenosine) as potential endogenous PARP inhibitors. We have found that purines (hypoxanthine > inosine > adenosine) dose-dependently inhibited PARP activation in peroxynitrite-treated macrophages and also inhibited the activity of the purified PARP enzyme. Consistently with their PARP inhibitory effects, the purines also protected interferon gamma + endotoxin (IFN/LPS) -stimulated RAW macrophages from the inhibition of mitochondrial respiration and inhibited nitrite production from IFN/LPS-stimulated macrophages. We have selected hypoxanthine as the most potent cytoprotective agent and PARP inhibitor among the three purine compounds, and investigated the mechanism of its cytoprotective effect. We have found that hypoxanthine protects thymocytes from death induced by the cytotoxic oxidant peroxynitrite. In line with the PARP inhibitory effect of purines, hypoxanthine has prevented necrotic cell death while increasing caspase activity and DNA fragmentation. As previously shown with other PARP inhibitors, hypoxanthine acted proximal to mitochondrial alterations as hypoxanthine inhibited the peroxynitrite-induced mitochondrial depolarization and secondary superoxide production. Our data imply that purines may serve as endogenous PARP inhibitors. We propose that, by affecting PARP activation, purines may modulate the pattern of cell death during shock, inflammation, and reperfusion injury.

Animals↗
PubMed2005

Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver.

This study was undertaken to identify nitric oxide synthase (NOS) isoforms responsible for the generation of cytoprotective NO during liver ischemic preconditioning (IPC). Sprague-Dawley rats were subjected to 45 min lobar ischemia followed by 2 h reperfusion. L-arginine or Nomega-nitro-L-arginine methyl ester (L-NAME) was administered to stimulate or block NO synthesis. Study groups (n=6) had 1) sham laparotomy, 2) ischemia reperfusion (IR), 3) IPC with 5 min ischemia and 10 min reperfusion before IR, 4) L-arginine before IR, or 5) L-NAME + IPC before IR. Liver function tests, nitrite + nitrate (NOx) and plasma amino acids were analyzed. The endothelial cell and inducible isoforms of NOS (eNOS and iNOS) were identified using immunohistochemistry and Western blotting. Both IPC and L-arginine treatment increased NOx (P<0.05) and improved serum liver enzymes (P<0.05) when compared with IR. These effects were prevented by L-NAME. Hepatic vein NOx was significantly higher than circulating NOx. iNOS expression was absent within the groups. The preconditioned livers were associated with up-regulation of eNOS expression and also increased L-arginine levels. The effects of L-arginine administration were similar to those evident following IPC. Thus, cytoprotective NO generation during IPC of the liver was a result of increased eNOS expression and increased L-arginine substrate availability.

Amino Acids↗
PubMed2003

Expression of A20 in the vessel wall of rat-kidney allografts correlates with protection from transplant arteriosclerosis.

BACKGROUND: Chronic rejection with development of transplant arteriosclerosis is the major culprit involved in loss of kidney allografts. The allografts' fate was thought to depend on the intensity of the host immune responses and the potency of immunosuppressive regimens. Recent data suggests that grafts contribute to their own survival by way of up-regulation of "cytoprotective" genes. METHODS: We analyzed the expression of four cytoprotective genes, A20, Bcl-2, Bcl-x(L) and heme oxygenase (HO)-1, in three rat renal allograft models of chronic rejection: Fisher 344-Lewis (F344/Lew), Dark Agouti-Brown Norway (DA/BN), and DA-Wistar-Furth (WF). We chose these genes for their known anti-inflammatory and anti-apoptotic function in endothelial cells (EC) and the atheroprotective function of A20 in smooth muscle cells (SMC). RESULTS: Twenty-eight and 9 weeks following transplantation, F344/Lew and DA/BN transplants had stable graft function. Histopathologic analysis showed moderate tissue damage, minimal cellular infiltrates, and preserved vascular integrity correlating with high expression of A20 in SMC. Conversely, impaired allograft function in the DA/WF combination with substantial transplant arteriosclerosis was noted in 60% of the grafts correlating with absent or decreased A20 expression in EC and SMC. In all combinations, expression of HO-1, Bcl-2, and Bcl-x(L) colocalized with infiltrating cells and was not informative on the graft status. CONCLUSIONS: We demonstrate for the first time a strict correlation between A20 expression in the vessel and the absence of transplant arteriosclerosis in rat kidney-allograft models. This data is similar to data obtained in human kidney allografts and suggests that A20 may represent a novel therapeutic target for the prevention of chronic allograft rejection.

Animals↗
PubMed2002

Preconditioning and adenosine protect human proximal tubule cells in an in vitro model of ischemic injury.

Renal ischemic reperfusion injury results in unacceptably high mortality and morbidity during the perioperative period. It has been recently demonstrated that ischemic preconditioning or adenosine receptor modulations attenuate renal ischemic reperfusion injury in vivo. An in vitro model of ischemic renal injury was used in cultured human proximal tubule (HK-2) cells to further elucidate the protective signaling cascades against renal ischemic reperfusion injury. ATP depletion preconditioning (1 h of antimycin A and 2-deoxyglucose treatment followed by 1 h of recovery), adenosine, an A(1) adenosine receptor selective agonist, or an A(2a) adenosine receptor selective agonist significantly attenuated subsequent severe ATP depletion injury of HK-2 cells. In contrast, an adenosine receptor antagonist failed to prevent protection induced by ATP depletion preconditioning. Cytoprotection by ATP depletion preconditioning or A(1) adenosine receptor activation was prevented by inhibitors of extracellular signal-regulated mitogen-activated kinases, protein kinase C, and tyrosine kinases. The A(1) and A(2a) adenosine receptor-mediated cytoprotection were also dependent on G(i/o) proteins and PKA activation, respectively. It is concluded that ATP depletion preconditioning and A(1) and A(2a) adenosine receptor activation protect HK-2 cells against severe ATP depletion injury via distinct signaling pathways.

Adenosine↗
PubMed2003

Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin.

Erythropoietin (EPO) plays a prominent role in the regulation of the hematopoietic system, but the potential function of this trophic factor as a cytoprotectant in the cerebral vascular system is not known. The authors examined the ability of EPO to modulate a series of death-related cellular pathways during free radical-induced injury in cerebral microvascular endothelial cells (ECs). Endothelial cell injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, apoptotic protease-activating factor-1 (Apaf-1), and Bcl-XL expression, mitochondrial membrane potential, cytochrome c release, and cysteine protease activity. They show that constitutive EPO is present in ECs but is insufficient to prevent cellular injury. Signaling through the EPO receptor, however, remains biologically responsive to exogenous EPO administration to offer significant protection against nitric oxide-induced injury. Exogenous EPO maintains both genomic DNA integrity and cellular membrane asymmetry through parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial membrane potential in conjunction with enhanced Bcl-XL expression. Consistent with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits the activation of caspase-9 and caspase-3-like activities. Identification of novel cytoprotective pathways used by EPO may serve as therapeutic targets for cerebral vascular disease.

Animals↗
PubMed2004

Role of NF-kappaB activation and nitric oxide expression during PGE protection against d-galactosamine-induced cell death in cultured rat hepatocytes.

Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction. Nitric oxide (NO) mediates PGE1 protection against D-galactosamine (D-GalN)-induced cell death. Nuclear factor kappa-B (NF-kappaB) plays a protective role in different experimental models of cell death. We investigated if NF-kappaB was responsible for inducible nitric oxide synthase (iNOS) expression and cytoprotection induced by PGE1 against D-GalN cell death in cultured hepatocytes. Rat hepatocytes were isolated following the classical method of collagenase perfusion of liver. A kinetic study of cell death, NF-kappaB activation, mRNA and protein iNOS expression, and NO production was carried in hepatocytes treated with D-GalN (5 mM) in the presence or absence of PGE1 (1 microM) administered 2 h before the hepatotoxin. A proteasome inhibitor was used to evaluate the role of NF-kappaB activation in our experimental conditions. PGE1 protection against D-GalN-induced cell death was associated with its capacity to rapidly enhance NF-kappaB activation, mRNA and protein iNOS expression, and NO production in D-GalN-treated hepatocytes. The inhibition of NF-kappaB activation abolished iNOS expression and cell protection by PGE1 in hepatocytes treated with the hepatotoxin. The present study shows that the cytoprotection by PGE1 against D-GalN-induced apoptosis was related to NF-kappaB-dependent iNOS expression.

Alprostadil↗
PubMed2003

Different faces of the heme-heme oxygenase system in inflammation.

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme

Animals↗