scholarly journals Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Simon C. M. Kwok
Keyword(s):  
Stress Response ◽  
Protein Kinase ◽  
Heme Oxygenase ◽  
Kinase Inhibitors ◽  
Protoporphyrin Ix ◽  
Competitive Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Transcriptional Level

Zinc protoporphyrin IX (ZnPP), a naturally occurring molecule formed in iron deficiency or lead poisoning, is a potent competitive inhibitor of heme oxygenase-1 (HO-1). It also regulates expression of HO-1 at the transcriptional level. However, the effect of ZnPP on HO-1 expression is controversial. It was shown to induce HO-1 expression in some cells, but suppress it in others. The objective of this study is to investigate the effect of ZnPP on HO-1 expression in prostate cancer PC-3 cells. Incubation of PC-3 cells with 10 μM ZnPP for 4 h showed only a slight induction of HO-1 mRNA and protein, but the induction was high after 16 h and was maintained through 48 h of incubation. Of all the known responsive elements in the HO-1 promoter, ZnPP activated mainly the stress response elements. Of the various protein kinase inhibitors and antioxidant tested, only Ro 31-8220 abrogated ZnPP-induced HO-1 expression, suggesting that activation of HO-1 gene by ZnPP may involve protein kinase C (PKC). The involvement of PKCα,β,δ,η,θ, andζisoforms was ruled out by the use of specific inhibitors. The isoform of PKC involved and participation of other transcription factors remain to be studied.

scholarly journals Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase

2005 ◽  
Vol 202 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Kanji Minamoto ◽  
Hiroaki Harada ◽  
Vibha N. Lama ◽  
Maksim A. Fedarau ◽  
David J. Pinsky
Keyword(s):  
Nitric Oxide ◽  
Heme Oxygenase ◽  
Soluble Guanylate Cyclase ◽  
Protoporphyrin Ix ◽  
Competitive Inhibitor ◽  
Binding Activity ◽  
Zinc Protoporphyrin ◽  
Reciprocal Regulation ◽  
Enhanced Expression ◽  
Lung Transplant Recipients

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8+ T cell–rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-κB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3′,5′-monophosphate–independent mechanism through which CO suppresses NF-κB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

scholarly journals Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats

2009 ◽  
Vol 110 (6) ◽  
pp. 1379-1389 ◽  
Author(s):  
Yueh-Hua Tai ◽  
Ru-Yin Tsai ◽  
Shinn-Long Lin ◽  
Chun-Chang Yeh ◽  
Jhi-Joung Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Heme Oxygenase ◽  
Antinociceptive Effect ◽  
Interleukin 10 ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Antiinflammatory Effect ◽  
Chronic Morphine ◽  
Mitogen Activated Protein

Background This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats. Methods Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days. Results Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats. Conclusions These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.

Endogenous zinc protoporphyrin formation critically contributes to hemorrhagic stroke-induced brain damage

2021 ◽  
pp. 0271678X2110284
Author(s):  
Rong Pan ◽  
Song Yu ◽  
Haikun Zhang ◽  
Graham S Timmins ◽  
John Weaver ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Kinase ◽  
Small Molecules ◽  
Brain Damage ◽  
Blood Cells ◽  
Hemorrhagic Stroke ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Zinc Protoporphyrin ◽  
Free Zinc

Hemorrhagic stroke is a leading cause of death. The causes of intracerebral hemorrhage (ICH)-induced brain damage are thought to include lysis of red blood cells, hemin release and iron overload. These mechanisms, however, have not proven very amenable to therapeutic intervention, and so other mechanistic targets are being sought. Here we report that accumulation of endogenously formed zinc protoporphyrin (ZnPP) also critically contributes to ICH-induced brain damage. ICH caused a significant accumulation of ZnPP in brain tissue surrounding hematoma, as evidenced by fluorescence microscopy of ZnPP, and further confirmed by fluorescence spectroscopy and supercritical fluid chromatography-mass spectrometry. ZnPP formation was dependent upon both ICH-induced hypoxia and an increase in free zinc accumulation. Notably, inhibiting ferrochelatase, which catalyzes insertion of zinc into protoporphyrin, greatly decreased ICH-induced endogenous ZnPP generation. Moreover, a significant decrease in brain damage was observed upon ferrochelatase inhibition, suggesting that endogenous ZnPP contributes to the damage in ICH. Our findings reveal a novel mechanism of ICH-induced brain damage through ferrochelatase-mediated formation of ZnPP in ICH tissue. Since ferrochelatase can be readily inhibited by small molecules, such as protein kinase inhibitors, this may provide a promising new and druggable target for ICH therapy.

Expression and function of heme oxygenase-1 in human gastric cancer

2012 ◽  
Vol 237 (4) ◽  
pp. 362-371 ◽  
Author(s):  
Yujing Yin ◽  
Qingjun Liu ◽  
Bo Wang ◽  
Gan Chen ◽  
Li Xu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Heme Oxygenase ◽  
Close Association ◽  
Protoporphyrin Ix ◽  
Clinicopathological Characteristics ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Human Gastric Cancer ◽  
Cobalt Protoporphyrin ◽  
And Function

Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues ( n = 74) and matched non-tumoral adjacent parenchyma ( n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis ( P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC.

scholarly journals Terminalia Chebulanin Attenuates Psoriatic Skin Lesion via Regulation of Heme Oxygenase-1

2016 ◽  
Vol 39 (2) ◽  
pp. 531-543 ◽  
Author(s):  
Jingang An ◽  
Tian Li ◽  
Yingying Dong ◽  
Zhengxiao Li ◽  
Jia Huo
Keyword(s):  
Heme Oxygenase ◽  
Therapeutic Option ◽  
Protoporphyrin Ix ◽  
Psoriatic Skin ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Keratinocyte Proliferation ◽  
Factor Α ◽  
Psoriatic Lesions

Background/Aims: Psoriasis is one of the most common inflammatory skin disorders, affecting 3% of the general population. Terminalia chebulanin (TC) is a polyphenolic compound that possesses antioxidant and anti-inflammatory activities. The current study was designed to investigate the effect of TC on psoriatic lesions. Methods: We examined the protective effect of TC against psoriatic lesions in mice and keratinocyte proliferation in HaCaT cells. Results: We found that TC exhibited potent anti-psoriatic activities, as evidenced by improvement of erythema and scaling scores, decrease of epidermal, ear and skinfold thickening, decrease of tumor necrosis factor α (TNFα), interleukin (IL)-17A, IL-23 and matrix metalloproteinase (MMP)-9 expression, and decrease of TBARS content and increase of GSH content in IMQ-treated mice, and decrease of keratinocyte proliferation, TNFα, IL-17A and IL-23 expression, and ROS level in M5-treated cells. All those effects induced by TC were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase (HO)-1, indicating that HO-1 was responsible the anti-psoriatic effect of TC. Moreover, TC inhibited the upregulation of p65 NF-κB under in vitro psoriatic condition. ZnPP suppressed TC-induced inhibition of p65 NF-κB expression. Overexpression of p65 NF-κB significantly suppressed TC-induced decrease of TNFα, IL-17A and IL-23 expression and keratinocyte proliferation, indicating that HO-1-mediated downregulation of NF-κB was involved in the anti-psoriatic effect of TC. Conclusions: The data demonstrate that TC may serve as a potential therapeutic option for psoriatic patients.

scholarly journals Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice

2006 ◽  
Vol 120 (3) ◽  
pp. 500-505 ◽  
Author(s):  
Kaeko Hirai ◽  
Tomonori Sasahira ◽  
Hitoshi Ohmori ◽  
Kiyomu Fujii ◽  
Hiroki Kuniyasu
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Heme Oxygenase ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
C57bl Mice

scholarly journals Carbon Monoxide Regulates Macrophage Differentiation and Polarization toward the M2 Phenotype through Upregulation of Heme Oxygenase 1

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3444
Author(s):  
In-Soon Kang ◽  
Rang-Ie Kim ◽  
Chaekyun Kim
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Bone Marrow Cells ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Macrophage Differentiation ◽  
Murine Bone Marrow ◽  
Arginase 1 ◽  
M2 Phenotype

Carbon monoxide (CO) is generated by heme oxygenase (HO), and HO-1 is highly induced in monocytes and macrophages upon stimulation. Monocytes differentiate into macrophages, including pro-inflammatory (M1) and anti-inflammatory (M2) cells, in response to environmental signals. The present study investigated whether CO modulates macrophage differentiation and polarization, by applying the CO-releasing molecule-3 (CORM-3). Results showed that murine bone marrow cells are differentiated into macrophages by CORM-3 in the presence of macrophage colony-stimulating factor. CORM-3 increases expressions of macrophage markers, including F4/80 and CD11b, and alters the cell morphology into elongated spindle-shaped cells, which is a typical morphology of M2 cells. CORM-3 upregulates the expressions of genes and molecules involved in M2 polarization and M2 phenotype markers, such as STAT6, PPARγ, Ym1, Fizz1, arginase-1, and IL-10. However, exposure to CORM-3 inhibits the iNOS expression, suggesting that CO enhances macrophage differentiation and polarization toward M2. Increased HO-1 expression is observed in differentiated macrophages, and CORM-3 further increases this expression. Hemin, an HO-1 inducer, results in increased macrophage differentiation, whereas the HO-1 inhibitor zinc protoporphyrin IX inhibits differentiation. In addition, CORM-3 increases the proportion of macrophages in peritoneal exudate cells and enhances the expression of HO-1 and arginase-1 but inhibits iNOS. Taken together, these results suggest that the abundantly produced CO in activated macrophages enhances proliferation, differentiation, and polarization toward M2. It will probably help clear apoptotic cells, resolve inflammation, and promote wound healing and tissue remodeling.

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