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The present study aimed to evaluate the protective effects of selenium (Sel) administration against tacrolimus (Tac) – induced lung toxicity and to assess the relation between heme oxygenase 1 (HO-1) and these effects. The study was conducted on 36 Wistar male albino rats equally divided into four groups: (i) normal control; (ii) Sel (0.1 mg/kg per day p.o. for four weeks); (iii) TAC 3 mg/mL as single oral dose on 27th day; and (iv) Tac + Sel. Lung tissues, lung homogenate, and bronchoalveolar lavage of the sacrificed animals were investigated biochemically and histopathologically, by immunohistochemistry or by PCR. The Tac group showed significantly lower expression of HO-1. Administration of Sel was associated with increased HO-1 expression. Oxidative (malondialdehyde, reduced glutathione, superoxide dismutase, myeloperoxidase, and glutathione peroxidase activity) and nitrosative stress (nitric oxide) markers and markers of inflammation (interleukin 1β (IL-1β), IL-6, and IL-10) showed changes corresponding to HO-1 levels in rat groups. Tac group showed the highest expression of caspase-3. Sel exerted a protective role against Tac-induced lung toxicity.

Objective To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. Methods The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress–related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. Results At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. Conclusion Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.

[Image: see text] Acute respiratory distress syndrome (ARDS) is one of the critical stages of COVID-19, leading to lung injury and hemolysis. Dysfunctional hemoglobin (Hb) suffers low-level oxygenation, overloaded iron, and down-regulation of hemeoxygenase-1 (HO-1), representing potential therapeutic interventions. This Viewpoint outlines the Hb–HO-1 system as a host-cell target, and proposes possible therapies, including iron chelation and CO therapies, against COVID-19 with ARDS.

Background: Most studies on air pollution (AP) exposure have focused on adverse health effects of particulate matter (PM). Less well-studied are the actions of volatile organic compounds (VOCs) not retained in PM collections. These studies quantified chemical and biological properties of both PM2.5 and VOCs. Methods: Samples were collected near the Port of Los Angeles (Long Beach, LB), railroads (Commerce, CM), and a pollution-trapping topography-site (San Bernardino, SB). Quantitative assays were conducted: (1) chemical&mdash, prooxidant and electrophile content, (2) biological&mdash, tumor necrosis factor-&alpha, (TNF-&alpha, ) and heme oxygenase-1 (HO-1) expression (3), VOC modulation of PM effects and (4), activation of the antioxidant response element (ARE) using murine RAW 264.7 macrophages. Results: SB site samples were the most potent in the chemical and biological assays, followed by a CM railroad site. Only PM2.5 exhibited significant proinflammatory responses. VOCs were more potent than PM2.5 in generating anti-inflammatory responses, further, VOC pretreatment reduced PM-associated TNF-&alpha, expression. VOCs significantly increased ARE activation compared to their corresponding PM2.5 which remained at background levels. Conclusion: Ambient VOCs are major contributors to adaptive responses that can modulate PM effects, in vitro, and, as such, need to be included in comprehensive assessments of AP.

To investigate the role of HO-1 in ischemic preconditioning and pharmacological preconditioning by ulinastatin in attenuating remote lung injury in rat model of lower limb ischemia reperfusion. Sixty four male SD rats were randomly divided into four groups: Sham operation group, ischemia and reperfusion group, ischemia preconditioning group (IPR), ulinastatin preconditioning group (UTI). The animals were deeply anesthetized and the lung tissue was removed at the end of the experiment. Lung W/D ratio were measured and the expression of HO-1 was determined by Immunohistochemical staining and western blotting. HO-1 was induced and expressed persistently in 2 and 4 h after ischemic preconditioning and ulinastatin preconditioning (P

Hemeoxygenase-1 induction in response to adverse circulatory conditions is protective. Our recent study has shown that administration of sirtinol attenuates hepatic injury in male Sprague-Dawley rats after trauma-hemorrhage; however, the mechanism by which sirtinol produces the salutary effects remains unknown. We hypothesized that sirtinol administration in male Sprague-Dawley rats after trauma-hemorrhage decreases cytokine production and protects against lung injury through a hemeoxygenase-1 related pathway.Male Sprague-Dawley rats (n = 8 per group) underwent trauma-hemorrhage (mean arterial blood pressure 40 mm Hg for 90 min, then resuscitation). A single dose of sirtinol (1 mg/kg of body weight) with or without a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin) or vehicle was administered IV during resuscitation. Twenty-four hours thereafter, myeloperoxidase activity (a marker of neutrophil sequestration) and tumor necrosis factor alpha, interleukin-6, and interleukin-10 levels in the lung, protein concentrations in bronchoalveolar lavage fluid and tissue histology were measured. Lung hemeoxygenase-1 protein level was also determined.In the sirtinol-treated rats subjected to trauma-hemorrhage, there were significant improvements in lung myeloperoxidase activity (4.68 +/- 0.31 vs 9.36 +/- 1.03 U/mg protein, P0.05), tumor necrosis factor alpha levels (710.7 +/- 28 vs 1288 +/- 40.69 pg/mg protein, P0.05), interleukin-6 levels (343.6 +/- 18.41 vs 592.7 +/- 22.3 pg/mg protein, P0.05), and protein concentrations (303.8 +/- 24.54 vs 569.6 +/- 34.82 microg/mL, P0.05) and lesser damage in histology. There was no statistically significant difference in interleukin-10 levels in the lung between sirtinol-treated trauma-hemorrhaged rats and vehicle-treated trauma-hemorrhaged rats (842.5 +/- 54.18 vs 756.2 +/- 41.34 pg/mg protein, respectively). Lung hemeoxygenase-1 protein levels were increased in rats receiving sirtinol treatment as compared with vehicle-treated trauma-hemorrhaged rats (5.18 +/- 0.25 vs 2.70 +/- 0.16, P0.05). Administration of the hemeoxygenase inhibitor chromium-mesoporphyrin prevented the sirtinol-induced attenuation of shock-induced lung damage.The salutary effects of sirtinol administration on attenuation of lung inflammation after trauma-hemorrhage are mediated via upregulation of hemeoxygenase-1 expression.

Objectives The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems. Methods The GENDER project is a multicenter prospective follow-up study, including 3146 patients after successful PCI. Genotyping in these patients was performed for the ACE gene insertion/deletion, the angiotensinogen 235Met/Thr, T174M and A(-6)G, the angiotensin-II type 1 receptor (AT1R) 1166A/C and T81OA, the angiotensin-II type 2 receptor (AT2R) 1675G/A and 3123A polymorphisms and the length polymorphism in the HO-1 promoter region. Results A total of 3104 patients were followed for 10 months. In 2975 patients at least one of the nine genotypes could be determined. The AT1R 1166 CC genotype showed a significant association with TVR; the other polymorphisms did not. RAS-inhibitory drugs were not associated with the incidence of TVR, nor did they interact with any of the investigated polymorphisms. Patients with the ACE I/I polymorphism showed a trend towards a better outcome if they had a short number of repeats in the HO-1 promoter. This relationship was inversely present in carriers of the ACE D/D polymorphism. Conclusion We could only establish a role for the AT1R 1166A/C polymorphism in restenosis after PCI. However, significant gene-gene interaction was suggested for the ACE gene and the HO-1 promotor. The RAS and HO-1 relation in restenosis merits further investigation. Pharmacogenetics and Genomics 16:331-337 (c) 2006 Lippincott Williams & Wilkins.

Patients with brain tumors suffer significant thrombotic morbidity and mortality. In addition to increased thrombin generation via tumor release of tissue factor-bearing microparticles and hyperfibrinogenemia, brain tumors and surrounding normal brain likely generate endogenous carbon monoxide (CO) via the hemeoxygenase-1 (HO-1) system. CO has been shown to enhance plasmatic coagulation via formation of carboxyhemefibrinogen (COHF). Thus, our goals in this study were to determine whether patients with brain tumors had increased HO-1 upregulation/CO production, plasmatic hypercoagulability, and formation of COHF.Patients with brain tumors (N = 20) undergoing craniotomy had blood collected for determination of carboxyhemoglobin as a marker of HO-1 activity, plasmatic hypercoagulability (defined as clot strength95% confidence interval value of normal subject plasma), and COHF formation (determined with a thrombelastograph-based assay). Plasma obtained from commercially available normal subjects (N = 30) was used for comparison with brain tumor patient samples.Brain tumor patients had carboxyhemoglobin concentrations of 1.5% ± 0.5% (mean ± SD), indicative of HO-1 upregulation. Compared with normal subject plasma, brain tumor patient plasma had significantly (P0.0001) greater clot formation velocity (5.2 ± 1.5 vs 9.5 ± 2.3 dynes/cm/s, respectively) and significantly (P = 0.00016) stronger final clot strength (166 ± 28 vs 230 ± 78 dynes/cm, respectively). Ten of the brain tumor patients had plasma clot strength that exceeded the 95% confidence interval value observed in normal subjects, and 12 of the brain tumor patients had COHF formation. Five of the brain tumor patients in the hypercoagulable subgroup had COHF formation. Last, 5 of the hypercoagulable patients had primary brain tumors, whereas the other 5 patients had metastatic tumors or an inflammatory mass lesion.A subset of patients with brain tumors has increased endogenous CO production, plasmatic hypercoagulability, and COHF formation. Future investigation of the role played by HO-1 derived CO in the pathogenesis of brain tumor-associated thrombophilia is warranted.

Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe2+), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe2+ 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe2+ increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe2+ treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe2+ group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe2+-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe2+ can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.

Recurring insulin-induced hypoglycemia (RIIH) often occurs during therapeutic management of insulin dependent diabetes mellitus. There is evidence that both cardiac and adrenergic sensitivity are altered in type 1 diabetics. Controversy currently exists in literature as to the ability of insulin to promote hypertension. Could insulin promote adverse pressor effects, if so under what conditions and through what mechanism? Thus, the current study was performed to evaluate the hypothesis that hypoglycemia promotes hypertension via an increase in Heme oxygenase-1 (HO-1). Male Sprague Dawley rats (200 – 225g) were treated for 2 weeks with varying doses of subcutaneous insulin injections (1, 3, 5, 7, and 9 U/kg body weight) and fed on normal chow or zinc diet (1mM) for 2 weeks. Tail-cuff blood pressure, food/water intake and blood glucose states were monitored daily. A dose dependent decrease in blood glucose was observed. Blood pressure was significantly elevated in rats treated with 7U/Kg dose as compared to ...

Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO-1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and α3β1-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and α3β1-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-κB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced-glomerular injury and apoptosis and these effects are associated with decreased NF-κB-induced inflammation and oxidative stress.

The complement cascade is activated and contributes to brain damage after intracerebral hemorrhage (ICH). The present study investigated ICH-induced brain damage in complement C3-deficient mice.