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Hyun-Ji Cho,
Jeong-Han Kang, Kwan-Kyu Park,
Jung-Yoon Choe,
Yoon-Yub Park,
Yong-Suk Moon,
Il-Kyung Chung,
Hyeun-Wook Chang,
Cheorl-Ho Kim,
Yung Hyun Choi,
Wun-Jae Kim,
Sung-Kwon Moon,
Young-Chae Chang
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ABSTRACT: BACKGROUND: Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. RESULTS: To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. CONCLUSION: Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent.
Proteome Science 05/2013; 11(1):20. · 2.33 Impact Factor
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Journal of Molecular Medicine 04/2013; · 4.67 Impact Factor
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ABSTRACT: C4d has been used as an evaluation marker for antibody-mediated rejection for solid organ transplantation. Although some studies have proposed that complement activation is involved in renal diseases, very little information is available on pathogenesis. This study was conducted to investigate C4d deposition in IgA nephropathy and to find its relations with histopathology and albuminuria.
This retrospective study included 23 patients who underwent renal biopsy at our medical center. The WHO grade of IgA nephropathy, interstitial inflammation and fibrosis, C4d staining and medical records including sex, age, and urine albumin were reviewed.
Thirteen patients (56.5%) were positive for C4d staining in the glomerulus and eleven patients (47.8%) were positive in the tubular epithelium. Glomerular C4d deposition was associated with albuminuria (p=0.044), and tubular C4d deposition was associated with a higher grade of IgA nephropathy (p=0.014).
Activation of the complement system was involved in renal damage and was identified through deposition of C4d in the glomerulus and tubules. Positive C4d staining in the glomerulus and the tubules may be associated with functional damage related to glomerular filtration and poor renal outcome.
International journal of clinical and experimental pathology 01/2013; 6(5):904-10. · 1.89 Impact Factor
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ABSTRACT: The pathophysiology of chronic renal disease is characterized by a progressive loss of renal function and deposition of the extracellular matrix, leading to widespread tissue fibrosis. Much of the matrix in chronic renal disease is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. These changes are believed to be derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. To develop a novel therapeutic approach for treating renal fibrosis, we examined the simultaneous inhibition of the transcription factors NF-κB and Sp1 in a mouse model of unilateral ureteral obstruction (UUO). To simultaneously inhibit both NF-κB and Sp1, we developed chimeric (Chi) decoy oligodeoxynucleotide (ODN) which contained binding sequences for both NF-κB and Sp1 in a single decoy molecule to enhance the effective use of decoy ODN strategy. Chi decoy ODN significantly attenuated tubulointerstitial fibrosis in a mouse model of UUO compared to scrambled decoy ODN, as demonstrated by the reduced interstitial volume, macrophage infiltration, and fibrosis-related gene expression. Interestingly, Chi decoy ODN also regulated EMT-related gene expression, leading to the inhibition of renal fibrotic changes in vivo and in vitro. The present study demonstrates the feasibility of Chi decoy ODN treatment for preventing renal fibrosis and EMT processes. This strategy might be useful to improve the clinical outcome after chronic renal disease.
Journal of Molecular Medicine 11/2012; · 4.67 Impact Factor
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ABSTRACT: Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-κB and Sp1 binding sites, to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODN were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.
Basic & Clinical Pharmacology & Toxicology 10/2012; · 2.18 Impact Factor
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Yun-Jeong Jeong,
Hyun-Ji Cho,
Key Whang,
In-Seon Lee, Kwan-Kyu Park,
Jung-Yoon Choe,
Sang-Mi Han,
Cheorl-Ho Kim,
Hyeun-Wook Chang,
Sung-Kwon Moon,
Wun-Jae Kim,
Yung Hyun Choi,
Young-Chae Chang
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ABSTRACT: Matrix metalloproteinases-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis and migration of vascular smooth muscle cells (VSMCs) after an arterial injury. In this study, we investigated the potential molecular mechanisms underlying the anti-atheroscleroic effects of melittin, a major component of bee venom, in human aortic smooth muscle cells (HASMCs). Melttin significantly suppressed MMP-9 and MMP-2 secretion, as well as TNF-α-induced MMP-9 expression in the HASMCs. In addition, we found that the inhibitory effects of melittin on TNF-α-induced MMP-9 protein expression are associated with the inhibition of MMP-9 transcription levels. Mechanistically, Melittin suppressed TNF-α-induced MMP-9 activity by inhibiting the phosphorylation of p38 and ERK1/2, but did not affect the phosphorylation of JNK and Akt. Reporter gene and western blotting assays showed that melittin inhibits MMP-9 transcriptional activity by blocking the activation of NF-κB via IκBα signaling pathway. Moreover, the matrigel migration assay showed that melittin reduced TNF-α-induced HASMC migration. These results suggest that melittin suppresses TNF-α-induced HASMC migration through the selective inhibition of MMP-9 expression and provide a novel role of melittin in the anti-atherosclerotic action.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 08/2012; 50(11):3996-4002. · 2.99 Impact Factor
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ABSTRACT: Background: Bee venom (Apis mellifera L., BV) possessing a rich source of pharmacologically active substances has the potential to be used as a cosmetic ingredient for antiaging, antiinflammatory and antibacterial functions. The aim of this study was to assess the skin sensitization of BV on experimental animals using the Buehler test. Materials and methods: Guinea pigs were randomly allocated into three groups of BV-sensitization, positive control-sensitization, and ethyl alcohol-sensitization group for induction and challenge. On the other hand, two groups of rats were administered with BV at doses of 0 and 1500 mg/kg. Clinical signs, mortality and body weight changes were continually monitored during the study period. Results: No treatment-related clinical signs or body weight changes were observed in both animal models. The average skin reaction evaluated by erythema and edema on the challenge sites, and sensitization rate in the BV-sensitization group of guinea pigs were substantially low compared with those in positive control group, representing a negligible sensitizing potential of BV. Conclusion: It was concluded that BV was well tolerated and exhibited no dermal irritation potential in guinea pigs and rats. Our findings may provide a developmental basis of BV for a cosmetic ingredient or external application for topical uses.
Cutaneous and Ocular Toxicology 07/2012; · 0.91 Impact Factor
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ABSTRACT: The development of atherosclerotic lesions is mainly due to macrophage death. The oxidative stresses of monocytes/macrophages play a vital role in the initiation and amplification of atherosclerosis. Apamin, a component of bee venom, exerts an anti-inflammatory effect, and selectively inhibits the Ca(2+)-activated K(+) channels. The mechanisms involved in the inhibition of macrophage apoptosis have been fully elucidated. We induced oxidized low-density lipoprotein (oxLDL) in THP-1-derived macrophage and studied the effect of apamin on intercellular lipid levels, mitochondria-related apoptotic pathway and numbers of apoptotic cells. Oil-red O staining indicates that the inhibition of apamin in the condition significantly prevents intracellular lipid deposition. Treatment with apamin significantly decreased the apoptotic macrophages by decreasing the expression of pro-apoptotic genes Bax, caspase-3 and PARP protein levels, as well as through increasing expression of anti-apoptotic genes Bcl-2 and Bcl-xL protein levels in the absence and presence of oxLDL. In vivo, with apamin treatment reduced apoptotic cells death by TUNEL staining. These results indicate that apamin plays an important role in monocyte/macrophage apoptotic processing, which may provide a potential drug for preventing atherosclerosis.
Experimental and Molecular Pathology 04/2012; 93(1):129-34. · 2.42 Impact Factor
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ABSTRACT: An infectious burden has been suggested to be associated with atherosclerosis in humans, based on the shared and underlying inflammatory responses during infection and atherosclerosis. However, the efficacy of anti-atherogenic drugs is yet to be tested against atherosclerosis in a scenario involving an infectious burden. We have examined alpha-lipoic acid (ALA) for anti-atherogenic effects in a hypercholesterolemic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with a hypercholesterolemic diet for 12 weeks to induce atherosclerosis. Lipopolysaccharide was intraperitoneally injected for the 1st week of study to simulate underlying infectious burden during development of atherosclerosis. ALA treatment alleviated atherosclerotic pathologies and reduced serum cholesterol and inflammatory cytokines. Consistently, atherosclerotic markers were improved by ALA treatment. In addition, ALA attenuated the proliferation and migration of vascular smooth muscle cells upon platelet-derived growth factor stimulation through the targeting of the Ras-MEK1/2-ERK1/2 pathway. This study demonstrates the efficacy of ALA on atherosclerosis with immunological complication, by showing that ALA modulates multiple pathogenic aspects of atherosclerosis induced by a hypercholesterolemic diet with inflammatory stimulation consisting of hypercholesterolemia, inflammation and VSMC activation.
Molecular Biology Reports 02/2012; 39(6):6857-66. · 2.93 Impact Factor
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ABSTRACT: Apamin, a peptide component of bee venom (BV), has anti-inflammatory properties. However, the molecular mechanisms by which apamin prevents atherosclerosis are not fully understood. We examined the effect of apamin on atherosclerotic mice. Atherosclerotic mice received intraperitoneal (ip) injections of lipopolysaccharide (LPS, 2 mg/kg) to induce atherosclerotic change and were fed an atherogenic diet for 12 weeks. Apamin (0.05 mg/kg) was administered by ip injection. LPS-induced THP-1-derived macrophage inflammation treated with apamin reduced expression of tumor necrosis factor (TNF)-α, vascular cell adhesion molecule (VCAM)-1, and intracellular cell adhesion molecule (ICAM)-1, as well as the nuclear factor kappa B (NF-κB) signaling pathway. Apamin decreased the formation of atherosclerotic lesions as assessed by hematoxylin and elastic staining. Treatment with apamin reduced lipids, Ca(2+) levels, and TNF-α in the serum from atherosclerotic mice. Further, apamin significantly attenuated expression of VCAM-1, ICAM-1, TGF-β1, and fibronectin in the descending aorta from atherosclerotic mice. These results indicate that apamin plays an important role in monocyte/macrophage inflammatory processing and may be of potential value for preventing atherosclerosis.
Evidence-based Complementary and Alternative Medicine 01/2012; 2012:305454. · 4.77 Impact Factor
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ABSTRACT: Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1α expression in response to EGF stimulation, but not in response to hypoxia (1% O(2)) or treatment with a transition metal (CoCl(2)). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1α expression, which suggested that ascochlorin inhibits HIF-1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1α expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis.
Journal of Cellular Biochemistry 11/2011; 113(4):1302-13. · 2.87 Impact Factor
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ABSTRACT: Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Following injury, an acute inflammation response takes place resulting in moderate cell necrosis and extracellular matrix damage. Melittin, the major bioactive component in the venom of honey bee Apis mellifera, is a 26-residue amphipathic peptide with well-known cytolytic, antimicrobial and proinflammatory properties. However, the molecular mechanisms responsible for the anti-inflammatory activity of melittin have not been elucidated in liver fibrosis. We investigated whether melittin ameliorates liver inflammation and fibrosis in thioacetamide (TAA)-induced liver fibrosis. Two groups of mice were treated with TAA (200 mg/L, in drinking water), one of the groups of mice was co-treated with melittin (0.1 mg/kg) for 12 weeks while the other was not. Hepatic stellate cells (HSCs) were cultured with tumor necrosis factor α in the absence or presence of melittin. Melittin suppresses the expression of proinflammatory cytokines through the nuclear factor (NF)-κB signaling pathway. Moreover, melittin reduces the activity of HSCs in vitro, and decreases the expression of fibrotic gene responses in TAA-induced liver fibrosis. Taken together, melittin prevents TAA-induced liver fibrosis by inhibiting liver inflammation and fibrosis, the mechanism of which is the interruption of the NF-κB signaling pathway. These results suggest that melittin could be an effective agent for preventing liver fibrosis.
Experimental Biology and Medicine 11/2011; 236(11):1306-13. · 2.64 Impact Factor
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Hyun-Ji Cho,
Jeong-Han Kang,
Ji-Hak Jeong,
Yun-Jeong Jeong, Kwan-Kyu Park,
Yoon-Yub Park,
Yong-Suk Moon,
Hong-Tae Kim,
Il-Kyung Chung,
Cheorl-Ho Kim,
Hyeun-Wook Chang,
Young-Chae Chang
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ABSTRACT: Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-β1 (TGF-β1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-β1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-β1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-β1-induced expression of PAI-1 without the inhibition of TβRII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.
Molecular Biology Reports 09/2011; 39(4):4597-603. · 2.93 Impact Factor
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ABSTRACT: Acute hepatic failure remains an extremely poor prognosis and still results in high mortality. Therefore, better treatment is urgently needed. Melittin, a major component of bee venom, is known to inhibit inflammatory reactions induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α in various cell types. However, there is no evidence of the anti-inflammatory and anti-apoptotic effect of melittin on liver cells. In the present study, we investigated the effects of melittin on D: -galactosamine (GalN)/lipopolysaccharide (LPS)-induced acute hepatic failure. Acute liver injury was induced with GalN/LPS to determine in vivo efficacy of melittin. Mice were randomly divided into four groups: sterile saline treated group (NC), melittin only treated group (NM), GalN/LPS-treated group (GalN/LPS), and GalN/LPS treated with melittin group (M+GalN/LPS). Mice were given intraperitoneal GalN/LPS with or without melittin treatment. Liver injury was assessed biochemically and histologically. Inflammatory cytokines in the serum, apoptosis of hepatocytes, and cleavage of caspase-3 in the liver were determined. The expression of TNF-α and interleukin (IL)-1β were increased in the GalN/LPS group. However, treatment of melittin attenuated the increase of inflammatory cytokines. The M+GalN/LPS group showed significantly fewer apoptotic cells compared to the GalN/LPS group. Melittin significantly inhibited the expression of caspase and bax protein levels as well as cytochrome c release in vivo. In addition, melittin prevented the activation of the transcription factor nuclear factor-kappa B (NF-κB) induced by GalN/LPS. These results clearly indicate that melittin provided protection against GalN/LPS-induced acute hepatic failure through the inhibition of inflammatory cytokines and apoptosis.
Apoptosis 09/2011; 17(1):61-9. · 4.07 Impact Factor
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ABSTRACT: Melittin is a cationic, hemolytic peptide that is the main toxic component in the venom of the honey bee (Apis mellifera). Melittin has multiple effects, including anti-bacterial, anti-viral and anti-inflammatory, in various cell types. However, the anti-apoptotic mechanisms of melittin have not been fully elucidated in hepatocytes. Apoptosis contributes to liver inflammation and fibrosis. Knowledge of the apoptotic mechanisms is important to develop new and effective therapies for treatment of cirrhosis, portal hypertension, liver cancer, and other liver diseases. In the present study, we investigated the anti-apoptotic effect of melittin on transforming growth factor (TGF)-β1-induced apoptosis in hepatocytes. TGF-β1-treated hepatocytes were exposed to low doses (0.5 and 1 μg/mL) and high dose (2 μg/mL) of melittin. The low doses significantly protected these cells from DNA damage in TGF-β1-induced apoptosis compared to the high dose. Also, melittin suppressed TGF-β1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase (PARP) cleavage. These results demonstrate that TGF-β1 induces hepatocyte apoptosis and that an optimal dose of melittin exerts anti-apoptotic effects against TGF-β1-induced injury to hepatocytes via the mitochondrial pathway. These results suggest that an optimal dose of melittin can serve to protect cells against TGF-β1-mediated injury.
Toxicology and Applied Pharmacology 08/2011; 256(2):209-15. · 4.45 Impact Factor
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Ji-Hak Jeong,
Jeong Han Kang,
Seung-Lark Hwang,
Hyun-Ji Cho, Kwan-Kyu Park,
Yoon-Yup Park,
Il-Kyung Chung,
Hyeun-Wook Chang,
Cheorl-Ho Kim,
Kwan-Sik Min,
Hong-Duck Kim,
Junji Magae,
Shin-Sung Kang,
Young-Chae Chang
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ABSTRACT: Chemopreventive or anticancer agents induce cancer cells to apoptosis through the activation of adenosine AMP-activated protein kinase (AMPK), which plays a major role as energy sensors under ATP-deprived condition or ROS generation. In this study, we compared the effects of ascochlorin (ASC), from the fungus Ascochyta viciae, and its derivatives on AMPK activity. We also examined a regulatory mechanism for hypoxia-inducible factor-1α (HIF-1α) stabilization in response to 4-O-methylascochlorin (MAC). We found that AMPK activation was mainly involved with MAC, but not ASC and 4-O-carboxymethylascochlorin (AS-6), indicating that the substitution of 4-O-methyl group from 4-O-hydroxyl group of ASC is important in the activation of AMPK and the expression of HIF-1α. MAC-stabilized HIF-1α via AMPK activation triggered by lowering the intracellular ATP level, not by ROS generation, increases glucose uptake and the expression of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), major target genes of HIF-1α. Moreover, MAC-induced AMPK activity suppressed survival factors, including mTOR and ERK1/2 or translational regulators, including p70S6K and 4E-BP1. Our data suggest that AMPK is a key determinant of MAC-induced HIF-1α expression in response to energy stress, further implying its involvement in MAC-induced apoptosis.
Biochemical and Biophysical Research Communications 02/2011; 406(3):353-8. · 2.48 Impact Factor
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ABSTRACT: Resistance to apoptosis of fibroblast-like synoviocytes (FLS) is considered as a major characteristic in RA. This study was designed to identify whether melittin has a pro-apoptotic effect in IL-6/sIL6R-stimulated human FLS by investigating the expression of mitochondrial apoptosis-related genes, nuclear factor-κB (NF-κB), and signal transducer and activators of transcription (STAT) activation.
Cell viability was determined using a MTT assay after melittin treatment. Expressions of STAT3 and mitochondrial apoptosis-related genes induced by the IL-6/sIL-6R complex were determined by real time-polymerase chain reaction and western blotting. The expression of NF-κB p65 following IL-6 stimulation was determined by western blot analysis. The effects of melittin on the expression of apoptosis-related genes and the transcription factors NF-κB p65 and STAT3 were assessed in FLS. Apoptosis of FLS was determined by TUNEL-labeling to detect DNA strand breaks and DNA fragmentation assays. Caspase-3 activity was determined by a colorimetric assay.
IL-6/sIL-6R induced the activation of the transcription factors, STAT3, NF-κB p65 (nucleus), and Bcl-2. Melittin increased the expression of pro-apoptosis-related molecules, namely caspase-3, caspase-9, Apaf-1, and cytosolic cytochrome c, in a dose-dependent manner after treatment with IL-6/sIL-6R. Melittin inhibited STAT3 activation, translocation of NF-κB p65 into the nucleus, and expression of anti-apoptotic genes such as Bcl-2 and mitochondrial cytochrome c.
The pro-apoptotic effects of melittin likely result from inhibition of the activation of the transcription factors, STAT3 and NF-κB p65, and regulation of mitochondrial apoptosis-related genes. Melittin is thus a promising therapeutic option for RA as it induces apoptosis in apoptosis-resistant synoviocytes.
Joint, bone, spine: revue du rhumatisme 02/2011; 78(5):471-7. · 2.25 Impact Factor
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ABSTRACT: Atherosclerosis is influenced by multiple environmental factors that involve a complex interaction between blood components and the arterial wall and is characterized by inflammatory reactions. Melittin has been used in treatment of various chronic inflammatory diseases. We investigated the effects of melittin regulated atherosclerotic changes in an animal model of atherosclerosis.
Atherosclerotic mice were induced by intraperitoneal (i.p) injection of lipopolysaccharide (LPS, 2 mg/kg) three times a week and an atherogenic diet for 12 weeks.
Melittin (0.1 mg/kg) treatment was administered with i.p injection. Melittin treatment showed that total cholesterol and triglyceride levels decreased in atherosclerotic mice however, high-density lipoprotein cholesterol (HDL-C) levels were higher in atherosclerotic mice treated with melittin than in atherosclerotic mice. H&E staining showed that heart and descending aorta were significantly recovered by melittin, compared to atherosclerotic mice. In addition, melittin decreased the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, fibronectin and transforming growth factor (TGF)-β1 in atherosclerotic mice. In vitro, melittin decreased LPS-induced THP-1 cells-derived macrophages TNF-α and IL-1β expression levels and nuclear factor (NF)-κB signal pathway.
These results demonstrate that melittin has an anti-atherogenic effect by suppression of pro-inflammatory cytokines and adhesion molecules.
Journal of atherosclerosis and thrombosis 01/2011; 18(12):1117-26. · 2.69 Impact Factor
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ABSTRACT: Atherosclerosis is a chronic inflammatory process occurring in the walls of arteries, in large part due to the accumulation of inflammatory cells. This study was conducted to determine the effect of nuclear factor (NF)-κB decoy oligodeoxynucleotide (ODN) in an atherosclerosis animal model. The mice received i.p. injections of lipopolysaccharide (LPS, 2 mg/kg) three times a week to induce atherosclerotic change, and fed an atherogenic diet for 12 weeks. NF-κB decoy ODN (0.4 mg/kg) was injected into the tail vein. Treatment with NF-κB decoy ODN decreased pro-inflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1β and inflammatory markers, vascular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, in the LPS/Fat-induced mice. In addition, the expression of proteins related to fibrosis, transforming growth factor (TGF)-β1 and fibronectin were markedly decreased in the mice treated with NF-κB decoy ODN compared with the LPS/Fat-induced mice without decoy ODN treatment. These data suggest that NF-κB decoy ODN may exert an inhibitory effect on the expression levels of pro-inflammatory cytokines and cell adhesion molecules in atherosclerotic mice.
Basic & Clinical Pharmacology & Toxicology 12/2010; 107(6):925-30. · 2.18 Impact Factor
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ABSTRACT: Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G(1) arrest without cytoxicity with upregulation of p53 and p21(WAF1/CIP1) while downregulating c-Myc and G(1) cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21(WAF1/CIP1) expression and subsequent G(1) arrest through the release of p21(WAF1/CIP1) promoter from c-Myc-mediated transcriptional repression, independent of p53. Ascofuranone-induced p21(WAF1/CIP1) associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21(WAF1/CIP1) through p53-independent suppression of c-Myc expression, leading to cytostatic G(1) arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53.
Molecular Cancer Therapeutics 07/2010; 9(7):2102-13. · 5.23 Impact Factor
