• Archives of Pharmacal Research
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• 제29권3호
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• pp.249-255
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• 2006

Ability of iron acquisition of pathogenic microorganisms functions as a virulence factor. Candida albicans, a fungal pathogen that requires iron for growth, is susceptible to growth retardation by high-affinity iron binding proteins such as transferrin. Recently, we reported that C. albicans could utilize the heme as a part of heme-containing proteins dissociated by heme oxygenase, CaHMX1. In search of another pathway that C. albicans can use to bypass the growth regulation produced by iron limitation, this present study examined utilization of non-candidal siderophores such as Desferal and rhodotorulic acid (RA) for acquisition of inorganic iron by the fungus. C. albicans secreting no siderophores was cultured in iron-free (pretreated with apotransferrin for 24 h) (culture medium). Once growth of the yeast reached stasis from iron starvation, a siderophore was added to the culture media. Results showed that cultures containing apotransferrin within a dialysis membrane recovered growth to the level of untreated controls, whereas C. albicans yeast cells in direct contact with soluble iron-free (apo) transferrin recovered growth only partially. When static growth from iron limitation was reached, the addition of siderophore-apotransferrin complex to culture medium also permitted the yeast to recover growth from apotransferrin growth regulation. All the data show that C. albicans can utilize the non-candidal siderophores for iron acquisition under transferrin regulation as can pathogenic bacteria.

• 대한지역사회영양학회지
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• 제3권1호
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• pp.53-61
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• 1998

This study was designed to estimate mean daily iron intake and its bioavailabi- lity and to assess nutrition knowledge for 144 pregnant women in the last trimester. Serum ferritin concentration was analyzed to estimate their iron stores. Dietary intakes of iron(heme iron and nonheme iron), the amounts of MPF(meat, poultry and fish) and ascorbic acid were assessed by modified 24-hr recall method. The food frequency questionnaire was used to assess subjects usual food consumption patterns. The mean value of serum ferritin was $21.3\pm{15.2ng/ml}$ and 26.4% of the pregnant women had a serum ferritin level <12ng/ml(i.e. depleted iron stores). The mean daily intake of total orin in the pregnant women was 56.5%(17.0mg) of RDA and heme iron intake was 0.94mg which was 5.5% of total iron intake. Total absorbable iron calculated by the method of Monsen was 2.41mg and bioavailability of dietary iron was 2.41%. Food frequency test score of meats group was positively correlated(r=0.443) with the bioaavailability of dietary iron. The mean score on the nutrition knowledge test of subjects was 12.76(out of a possible 20 points). These results indicate that the nutritional iron status may be improved by increasing either the amount of iron in the diet or its availability.

• 동의생리병리학회지
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• 제28권1호
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• pp.63-68
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• 2014

The fruit of Tribulus terrestris L. (Zygophyllaceae) is an important source of traditional Korean and Chinese medicines. In this study, NNMBS223, consisting of the ethanol extract of T. terrestris, showed potent anti-inflammatory activities in RAW264.7 macrophages. We investigated the effect of NNMBS223 in suppressing the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and production of iNOS-derived nitric oxide (NO), COX-2-derived prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated macrophages. In addition, NNMBS223 induced expression of heme oxygenase (HO)-1 through nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in macrophages. The effects of NNMBS223 on LPS-induced production of NO and PGE2 were partially reversed by the HO activity inhibitor tin protoporphyrin (SnPP). These findings suggest that Nrf2-dependent increases in expression of HO-1 induced by NNMBS223 conferred anti-inflammatory activities in LPS stimulated RAW264.7 macrophages.

• Journal of Microbiology and Biotechnology
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• 제28권8호
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• pp.1310-1317
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• 2018

The stems of Dendrobium moniliforme have been used in traditional herbal medicine for the treatment of fever and lack of body fluid in Korea. In this study, we investigated anti-inflammatory effects of the aqueous extract of D. moniliforme stems (DM) in response to lipoteichoic acid (LTA), a major constituent of the cell wall of Gram-positive bacteria. DM inhibited LTA-induced expression of a pro-inflammatory mediator inducible nitric oxide synthase (iNOS) in the murine macrophages. And DM induced expression of heme oxygenase-1 (HO-1) at the transcriptional level. Conversely, the knockdown of HO-1 expression by siRNA markedly reversed the inhibitory effects of DM on LTA-induced iNOS expression. We also demonstrated that nuclear translocation of Nrf2 was increased following treatment with DM. In addition, DM-mediated Nrf2 activation and HO-1 expression were suppressed by PI3K/Akt and p38 inhibitors; treatment with DM also resulted in phosphorylation of Akt and p38. These results suggest that DM inhibits the expression of iNOS in LTA-stimulated macrophages, and that these effects are mediated by the upregulation of HO-1 expression via PI3K/Akt/p38-Nrf2 signaling.

• The Korean Journal of Physiology and Pharmacology
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• 제19권4호
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• pp.327-334
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• 2015

The cytoprotective enzyme heme oxygenase-1 (HO-1) influences endothelial cell survival, proliferation, inflammatory response, and angiogenesis in response to various angiogenic stimuli. In this study, we investigate the involvement of HO-1 in the angiogenic activity of orexin-A. We showed that orexin-A stimulates expression and activity of HO-1 in human umbilical vein endothelial cells (HUVECs). Furthermore, we showed that inhibition of HO-1 by tin (Sn) protoporphryin-IX (SnPP) reduced orexin- A-induced angiogenesis in vivo and ex vivo. Orexin-A-stimulated endothelial tube formation and chemotactic activity were also blocked in SnPP-treated vascular endothelial cells. Orexin-A treatment increased the expression of nuclear factor erythroid-derived 2 related factor 2 (Nrf2), and antioxidant response element (ARE) luciferase activity, leading to induction of HO-1. Collectively, these findings indicate that HO-1 plays a role as an important mediator of orexin-A-induced angiogenesis, and provide new possibilities for therapeutic approaches in pathophysiological conditions associated with angiogenesis.

• 생약학회지
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• 제41권3호
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• pp.190-195
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• 2010

Glutamate-induced oxidative injury contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemia. Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a role in the pathogenesis of these diseases. NNMBS098, a composition comprising the water insoluble of the 70% EtOH extract of Zingiberis Rhizoma, showed the potent neuroprotective effects on glutamateinduced neurotoxicity by induced the expression of heme oxygenase (HO)-1 and increased HO activity in the mouse hippocampal HT22 cells. Furthermore, NNMBS098 caused the nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2) in mouse hippocampal HT22 cells. In addition, we found that treatment with c-Jun N-terminal kinase (JNK) inhibitor (SP600125) reduced NNMBS098-induced HO-1 expression and NNMBS098 also increased JNK phosphorylation. Therefore, these results suggest that NNMBS098 increases cellular resistance to glutamate-induced oxidative injury in mouse hippocampal HT22 cells, presumably through JNK pathway-Nrf2-dependent HO-1 expression.

• 동의생리병리학회지
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• 제20권5호
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• pp.1334-1336
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• 2006

Effects of twenty-three aqueous herbal extracts used in oriental medicines on heme oxygenase (HO)-1 expression were estimated in a mouse hippocampal cell line, HT22. HO-1 is one of the cytoprotective enzymes activated various stimuli, and Western blot analysis was used for evaluated HO-1 expression. Six aqueous extracts such as Rhei Rhizoma, Paeoniae Radix, Uncariae Ramulus et Uncus, Theae Folium, Prunellae Spica, and Coptidis Rhizoma significantly increased HO-1 expression in HT22 cells at the concentration of 300 ${\mu}$g/ml. In Addition, four aqueous extracts including Eucommiae Cortex, Moutan Cortex Radicis, Ginseng Radix Rubra, and Scutellariae Radix moderately increased HO-1 expression. These results would be usefulfor the isolation and identification of their neuroprotective principles.

• Journal of Cancer Prevention
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• 제21권3호
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• pp.135-143
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• 2016

Background: Fraxetin (7,8-dihydroxy-6-methoxy coumarin), a coumarin derivative, has been reported to possess antioxidative, anti-inflammatory and neuroprotective effects. A number of recent observations suggest that the induction of heme oxygenase-1 (HO-1) inhibits inflammation and tumorigenesis. In the present study, we determined the effect of fraxetin on HO-1 expression in HaCaT human keratinocytes and investigated its underlying molecular mechanisms. Methods: Reverse transcriptase-PCR and Western blot analysis were performed to detect HO-1 mRNA and protein expression, respectively. Cell viability was measured by the MTS test. The induction of intracellular reactive oxygen species (ROS) by fraxetin was evaluated by 2′,7′-dichlorofluorescin diacetate staining. Results: Fraxetin upregulated mRNA and protein expression of HO-1. Incubation with fraxetin induced the localization of nuclear factor-erythroid-2-related factor-2 (Nrf2) in the nucleus and increased the antioxidant response element-reporter gene activity. Fraxetin also induced the phosphorylation of Akt and AMP-activated protein kinase $(AMPK){\alpha}$ and diminished the expression of phosphatase and tensin homolog, a negative regulator of Akt. Pharmacological inhibition of Akt and $AMPK{\alpha}$ abrogated fraxetin-induced expression of HO-1 and nuclear localization of Nrf2. Furthermore, fraxetin generated ROS in a concentration-dependent manner. Conclusions: Fraxetin induces HO-1 expression through activation of Akt/Nrf2 or $AMPK{\alpha}/Nrf2$ pathway in HaCaT cells.

• Journal of Microbiology and Biotechnology
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• 제29권1호
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• pp.11-20
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• 2019

Ecklonia cava, an edible marine brown alga (Laminariaceae), is a rich source of bioactive compounds such as fucoidan and phlorotannins. Ecklonia cava extract (ECE) was prepared using 70% ethanol extraction and ECE contained 67% and 10.6% of total phlorotannins and dieckol, respectively. ECE treatment significantly inhibited receptor activator of nuclear $factor-{\kappa}B$ ligand (RANKL)-induced osteoclast differentiation of RAW 264.7 cells and pit formation in bone resorption assay (p <0.05). Moreover, it suppressed RANKL-induced $NF-{\kappa}B$ and mitogen-activated protein kinase signaling in a dose dependent manner. Downregulated osteoclast-specific gene (tartrate-resistant acid phosphatase, cathepsin K, and matrix metalloproteinase-9) expression and osteoclast proliferative transcriptional factors (nuclear factor of activated T cells-1 and c-fos) confirmed ECE-mediated suppression of osteoclastogenesis. ECE treatment ($100{\mu}g/ml$) increased heme oxygenase-1 expression by 2.5-fold and decreased intercellular reactive oxygen species production during osteoclastogenesis. The effective inhibition of RANKL-stimulated osteoclast differentiation and oxidative stress by ECE suggest that ECE has therapeutic potential in alleviating osteoclast-associated disorders.

• Biomolecules & Therapeutics
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• 제31권5호
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• pp.526-535
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• 2023

Breast cancer is the most common cancer and a frequent cause of cancer-related deaths among women wordlwide. As therapeutic strategies for breast cancer have limitations, novel chemotherapeutic reagents and treatment strategies are needed. In this study, we investigated the anti-cancer effect of synthetic homoisoflavane derivatives of cremastranone on breast cancer cells. Homoisoflavane derivatives, SH-17059 and SH-19021, reduced cell proliferation through G2/M cell cycle arrest and induced caspase-independent cell death. These compounds increased heme oxygenase-1 (HO-1) and 5-aminolevulinic acid synthase 1 (ALAS1), suggesting downregulation of heme. They also induced reactive oxygen species (ROS) generation and lipid peroxidation. Furthermore, they reduced expression of glutathione peroxidase 4 (GPX4). Therefore, we suggest that the SH-17059 and SH-19021 induced the caspase-independent cell death through the accumulation of iron from heme degradation, and the ferroptosis might be one of the potential candidates for caspase-independent cell death.