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 Rosmarinic acid protects against ulcerative colitis by regulating macrophage polarization depending on heme oxygenase-1 in mice

2020 ◽  
Vol 18 ◽  
pp. 205873922095991
Author(s):  
Ping Mai ◽  
Cheng Chen ◽  
Xiaohui Xiao ◽  
Xin Ma ◽  
Yuping Shi ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Heme Oxygenase ◽  
Rosmarinic Acid ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Alternative Activation ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
M1 Polarization

Ulcerative colitis (UC) is an unknown-cause inflammatory disease of colorectum. At present, there are no specific therapeutic drugs. We found that rosmarinic acid (RA) can significantly improve UC and further explored the relevant cellular and molecular mechanisms. Firstly, using F4/80 as marker for mouse macrophages, we found there were large numbers of macrophages infiltrating into colonic tissue of dextran sulfate sodium (DSS)-induced mice UC model. Meanwhile, RA markedly improved weight loss, diarrhea, hematochezia and colonic inflammation in mice with DSS treatment. Further, RA changed macrophage polarization in mouse colon, showing that classical activation (M1) phenotype decreased, alternative activation (M2) phenotype increased, and M1/M2 ratio reversed by Real-time PCR. In vitro, we cultured the peripheral blood macrophages (PBM) and found that RA inhibited PBM M1 polarization and favored M2 polarization directly. Heme oxygenase-1 (HO-1) mediated the anti-inflammatory effect of RA. RA induced HO-1 expression in PBM, and the HO-1 inhibitor, zinc protoporphyrin, blunted the inhibitory effect of RA on lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-κB) translocation and M1 polarization. In addition, blocking NF-κB signal has no effect on the role of RA. In conclusion, RA protects against UC by regulating macrophage polarization depending on HO-1. These data suggest that reversing macrophage polarization can be used as a strategy for UC treatment and RA is an effective drug to cure UC by regulating macrophage polarization.

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 Effects of Metalloporphyrins on Heme Oxygenase-1 Transcription: Correlative Cell Culture Assays Guide in Vivo Imaging

2003 ◽  
Vol 2 (3) ◽  
pp. 153535002003031
Author(s):  
Monica Hajdena-Dawson ◽  
Weisheng Zhang ◽  
Pamela R. Contag ◽  
Ronald J. Wong ◽  
Hendrik J. Vreman ◽  
...  
Keyword(s):  
Cell Culture ◽  
Heme Oxygenase ◽  
Liver Toxicity ◽  
Whole Body ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Live Animal ◽  
Cytotoxicity Studies

Heme oxygenase (HO) is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps), a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI) as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP) and zinc bis glycol porphyrin (ZnBG), were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.

scholarly journals Cannabinoid-Induced Autophagy and Heme Oxygenase-1 Determine the Fate of Adipose Tissue-Derived Mesenchymal Stem Cells under Stressful Conditions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2298
Author(s):  
Katharina Bublitz ◽  
Sabine Böckmann ◽  
Kirsten Peters ◽  
Burkhard Hinz
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Heme Oxygenase ◽  
Metabolic Activity ◽  
Therapeutic Option ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Serum Free ◽  
Serum Free Conditions

The administration of adipose tissue-derived mesenchymal stem cells (ADMSCs) represents a promising therapeutic option after myocardial ischemia or myocardial infarction. However, their potential is reduced due to the high post-transplant cell mortality probably caused by oxidative stress and mitogen-deficient microenvironments. To identify protection strategies for ADMSCs, this study investigated the influence of the non-psychoactive phytocannabinoid cannabidiol (CBD) and the endocannabinoid analogue R(+)-methanandamide (MA) on the induction of heme oxygenase-1 (HO-1) and autophagy under serum-free conditions. At a concentration of 3 µM, CBD induced an upregulation of HO-1 mRNA and protein within 6 h, whereas for MA only a late and comparatively lower increase in the HO-1 protein could be detected after 48 h. In addition, both cannabinoids induced time- and concentration-dependent increases in LC3A/B-II protein, a marker of autophagy, and in metabolic activity. A participation of several cannabinoid-binding receptors in the effect on metabolic activity and HO-1 was excluded. Similarly, knockdown of HO-1 by siRNA or inhibition of HO-1 activity by tin protoporphyrin IX (SnPPIX) had no effect on CBD-induced autophagy and metabolic activity. On the other hand, the inhibition of autophagy by bafilomycin A1 led to a significant decrease in cannabinoid-induced metabolic activity and to an increase in apoptosis. Under these circumstances, a significant induction of HO-1 expression after 24 h could also be demonstrated for MA. Remarkably, inhibition of HO-1 by SnPPIX under conditions of autophagy deficit led to a significant reversal of apoptosis in cannabinoid-treated cells. In conclusion, the investigated cannabinoids increase metabolic viability of ADMSCs under serum-free conditions by inducing HO-1-independent autophagy but contribute to apoptosis under conditions of additional autophagy deficit via an HO-1-dependent pathway.

Upregulation of heme oxygenase-1 potentiates EDH-type relaxations in the mesenteric artery of the spontaneously hypertensive rat

2013 ◽  
Vol 305 (10) ◽  
pp. H1471-H1483 ◽  
Author(s):  
Zhuoming Li ◽  
Yu Wang ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Spontaneously Hypertensive Rat ◽  
Combined Treatment ◽  
Antioxidant Properties ◽  
Mesenteric Arteries ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Spontaneously Hypertensive

Heme oxygenase (HO) converts heme to carbon monoxide, bilirubin, and free iron. The present study investigated whether or not HO-1 induction improves vascular relaxations attributable to endothelium-dependent hyperpolarization (EDH). Thirty-six-week-old spontaneously hypertensive rats were treated with the HO-1 inducer hemin, the HO inhibitor zinc protoporphyrin IX (II) (ZnPP), the antioxidant apocynin, or combinations of these compounds. Isolated mesenteric arteries were prepared for measurement of isometric tension, protein presence, and production of reactive oxygen species (ROS). Hemin potentiated acetylcholine-evoked EDH-type relaxations in the presence of Nω-nitro-l-arginine methyl ester (l-NAME) and indomethacin, while the combined treatment with ZnPP plus hemin prevented these improvements. The intermediate conductance Ca2+-activated K+ channel (IKCa) blocker TRAM-34 and the Na+-K+-ATPase blocker ouabain significantly impaired these hemin-potentiated relaxations. NS309-induced TRAM-34- and ouabain-sensitive relaxations were enhanced by hemin. K+-induced ouabain-sensitive relaxations and the expression of Na+-K+-ATPase were increased by hemin. Thus HO-1 induction improves EDH-type relaxations by augmented activation of IKCa and the downstream Na+-K+-ATPase. Treatment with apocynin showed a similar effect as hemin in impairing ROS production, enhancing K+-induced relaxations, and increasing Na+-K+-ATPase expression, without affecting the expression of HO-1. The effects of hemin and apocynin were not additive. These observations suggest that the effect of HO-1 induction on EDH-type relaxations is possibly due to its antioxidant properties. In vitro treatment with bilirubin, but not carbon monoxide, enhanced EDH-type relaxations and K+-induced ouabain-sensitive relaxations, suggesting that the production of bilirubin may be also involved. The present findings reveal that HO-1 may be a potential vascular-specific therapeutic strategy for endothelial dysfunction in hypertension.

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 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 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.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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