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1.
Eur Rev Med Pharmacol Sci ; 26(8): 2794-2801, 2022 04.
Article in English | MEDLINE | ID: mdl-35503624

ABSTRACT

OBJECTIVE: The nitric oxide (NO) metabolite nitrite has been shown to attenuate hyperglycemia via its increase in insulin sensitivity and glucose uptake. However, the oral use of nitrite is limited due to its potential formation of the carcinogenic N-nitrosamines via reaction of acidic nitrite and the secondary amines. We investigated the anti-diabetic effect of sodium nitrite (SN) combined with glutathione (GSH) in streptozotocin (STZ)-induced diabetic mice for potential use of GSH as a protective agent in future nitrite therapy. MATERIALS AND METHODS: STZ-induced diabetic mice were orally treated for 5 weeks with vehicle, SN, GSH or SN + GSH. Oral glucose tolerance test and the measurement of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were carried out to evaluate anti-diabetic effects of SN and SN + GSH. Plasma levels of total NO metabolites (NOx) were measured to confirm nitrite absorption. RESULTS: SN and SN + GSH significantly improved the glucose tolerance (p < 0.05), but GSH alone did not. The efficacy of combination treatment with SN and GSH in improving the glucose tolerance was higher than that of SN alone. Oral treatment with SN or SN + GSH significant reduced FBG and HbA1c levels (p < 0.05). Interestingly, daily oral administration of SN + GSH was more effective in reducing FBG and HbA1c levels than that of SN alone. Administration of SN or SN + GSH significantly increased plasma NOx levels (p < 0.05), and combination treatment with SN + GSH was more effective in increasing plasma NOx levels than that with SN alone. CONCLUSIONS: Combination treatment with SN and GSH is more effective in controlling hyperglycemia and increasing the plasma NOx levels in an experimental mouse model of diabetes. Since oral administration of GSH has been shown to be non-toxic in humans, the combination of SN and GSH may be important in potential future nitrite therapy.


Subject(s)
Diabetes Mellitus, Experimental , Glutathione , Hyperglycemia , Sodium Nitrite , Animals , Antioxidants/administration & dosage , Antioxidants/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Glutathione/administration & dosage , Glycated Hemoglobin/metabolism , Hyperglycemia/drug therapy , Mice , Nitric Oxide/metabolism , Sodium Nitrite/administration & dosage , Streptozocin
2.
Eur Rev Med Pharmacol Sci ; 21(4): 890-899, 2017 02.
Article in English | MEDLINE | ID: mdl-28272690

ABSTRACT

OBJECTIVE: Nephrotoxicity is one of the major side effects that limit the use of cisplatin in cancer therapy. Cisplatin-induced apoptosis in renal cells is associated with reactive oxygen species (ROS)-mediated p53 activation. Licorice (Glycyrrhiza uralensis Fischer) is one of the most widely used medicinal herbs in Korea, China and Japan. The aim of the study was to evaluate the protective effects of licorice extract (LE) and its active compound glycyrrhizic acid (GA) against cisplatin-induced nephrotoxicity in human renal proximal tubular epithelial (HK-2) cells. MATERIALS AND METHODS: HK-2 cells were pretreated with LE or GA for 1 h and then treated with 40 µM of cisplatin for indicated times under the serum-free condition. Cell viability was evaluated by MTT assay. Apoptosis was evaluated by flow cytometric analysis and caspase-3 activity. The intracellular ROS levels were determined by DCFH-DA assay. The expression and phosphorylation levels of protein were evaluated by Western blot and densitometry analysis. RESULTS: When treating HK-2 cells with LE or GA, both of them alleviated cisplatin-induced cytotoxicity and apoptosis. LE and GA inhibited caspase-3 activity and polymerase (PARP) cleavage in cisplatin-treated cells. LE and GA also inhibited p53 expression and its phosphorylation as well as ROS production in cells exposed to cisplatin. Meanwhile, LE and GA enhanced cisplatin-induced p21 expression, which then led to S-phase arrest in cell cycle and limited cell growth. Presumably, increased p21 expression may contribute to cellular prevention from cisplatin-induced apoptosis, because p21 is the key molecule to cytoprotection during cisplatin-induced nephrotoxicity. CONCLUSIONS: These results suggest that LE and GA ameliorate cisplatin-induced apoptosis through reduction of ROS-mediating p53 activation and promotion of p21 expression in HK-2 cells.


Subject(s)
Cisplatin/adverse effects , Epithelial Cells/drug effects , Glycyrrhizic Acid/pharmacology , Plant Extracts/pharmacology , Reactive Oxygen Species/metabolism , Antineoplastic Agents/adverse effects , Apoptosis/drug effects , Cell Line , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Epithelial Cells/metabolism , Glycyrrhiza/chemistry , Humans , Kidney Tubules, Proximal/cytology , Tumor Suppressor Protein p53/metabolism
3.
Eur Rev Med Pharmacol Sci ; 19(16): 3125-32, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26367737

ABSTRACT

OBJECTIVE: Endothelial dysfunction associated with many cardiovascular diseases is largely due to reduced nitric oxide (NO) derived from endothelial NO synthase (eNOS). Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene; Pic) is reported to have cardiovascular therapeutic effects. However, the cellular and molecular mechanisms underlying the cardioprotective effects of Pic are still unclear. Here, we investigated whether Pic could influence endothelial NO release in human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: In HUVECs exposed to Pic, NO production and phosphorylation of eNOS and protein kinase B (Akt) were determined by using a commercially available NO assay kit and Western blot analysis, respectively. RESULTS: Pic stimulated dose- and time-dependent NO production via eNOS phosphorylation. Pic also stimulated dose-dependent phosphorylation of Akt. Interestingly, NO production and eNOS phosphorylation in response to Pic were significantly abolished by the phosphoinositide 3-kinase (PI3K)/Akt inhibitor LY294002. CONCLUSIONS: Pic is capable of inducing eNOS phosphorylation and the subsequent NO release, presumably, by activating PI3K/Akt pathway. The potential efficacy of Pic, a natural hydroxylated analog and a metabolite of resveratrol, may aid in the prevention of cardiovascular diseases characterized by endothelial dysfunction.


Subject(s)
Endothelial Cells/drug effects , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/metabolism , Stilbenes/pharmacology , Cells, Cultured , Endothelial Cells/enzymology , Endothelial Cells/metabolism , Humans , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects
4.
Eur Rev Med Pharmacol Sci ; 19(12): 2303-10, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26166660

ABSTRACT

OBJECTIVE: Indoxyl sulfate (IS) has been reported to induce endoplasmic reticulum (ER) stress in tubular cells and to inhibit the cell proliferation via ER stress and ERK/IL-6/p21 pathways. This study has investigated the effect of apigenin on IS-induced ER stress in immortalized human renal proximal tubular HK-2 cells. MATERIALS AND METHODS: Human Kidney 2 (HK-2) cells were treated with IS (5 mM) in the absence or presence of apigenin (10 µM) or salubrinal (20 µM) for indicated times under the serum-free condition. Cell viability was evaluated by MTT assay. The levels of protein expression and phosphorylation were evaluated by Western blot analysis. RESULTS: In HK-2 cells, apigenin completely inhibited IS-induced ER stress, as indicated by decreased expression of CHOP, ATF4 and GRP78, although the phosphorylated level of eIF2α did not decrease. IS-induced expression levels of IL-6 and p21 proteins were also inhibited by apigenin, with no significant changes in ERK activation. The suppression of cell proliferation by IS was abolished by salubrinal, an ER stress inhibitor, but not by apigenin. Apigenin inhibited the phosphorylation of Akt and GSK-3ß in IS-treated HK-2 cells. The phosphorylation of GSK-3ß, which was inhibited by apigenin, resulted in hypo-phosphorylation of retinoblastoma (Rb) protein, which was associated with the decrease in cyclin D1 expression. CONCLUSIONS: These results suggest that apigenin may inhibit IS-induced ER stress and expression of IL-6 and p21 proteins in HK-2 cells. It is most likely that apigenin, together with its inhibitory effect on ER stress, may also suppress the cell growth by inducing the loss of Rb phosphorylation, which was associated with the decrease in cyclin D1 expression by GSK-3ß activation through the inhibition of PI3K/Akt pathway.


Subject(s)
Apigenin/pharmacology , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Endoplasmic Reticulum Stress/physiology , Indican/toxicity , Interleukin-6/biosynthesis , Kidney Tubules, Proximal/metabolism , Transcription Factor CHOP/biosynthesis , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Line, Transformed , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cyclin-Dependent Kinase Inhibitor p21/antagonists & inhibitors , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Humans , Indican/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Kidney Tubules, Proximal/drug effects , Transcription Factor CHOP/antagonists & inhibitors
5.
Eur Rev Med Pharmacol Sci ; 18(8): 1135-41, 2014.
Article in English | MEDLINE | ID: mdl-24817286

ABSTRACT

BACKGROUND AND OBJECTIVES: Nephrotoxicity is one of the main side effects of the anticancer drug cisplatin, and one of its main therapeutic limitations. It has been suggested that p53 activation plays important roles in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study examined whether reactive oxygen species (ROS) production by cisplatin would be linked to p53 activation in rat mesangial cells. MATERIALS AND METHODS: Renal cells were incubated with cisplatin in the absence or presence of pifithrin-a (PFT), N-acetyl-cysteine (NAC), or dimethylthiourea (DMT). Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazol yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was evaluated by caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). The relative levels of ROS and p53 phosphorylation were determined by fluorometric assay and Western blot analysis, respectively. RESULTS: Cisplatin induced apoptotic cell death via caspase-3 activation and PARP cleavage, and also increased p53 activation and ROS production. The p53 inhibitor PFT inhibited cisplatin-induced apoptosis. NAC and DMT, two antioxidants, also inhibited cisplatin-induced apoptosis. Interestingly, NAC and DMT reduced ROS production and suppressed p53 activation in renal cells exposed to cisplatin. CONCLUSIONS: Our results suggest that the ability of cisplatin to induce apoptosis of rat mesangial cells requires ROS-dependent p53 activation, thus, supporting the potential therapeutic role of antioxidants in preventing the cisplatin nephrotoxicity.


Subject(s)
Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cisplatin/toxicity , Mesangial Cells/drug effects , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Antioxidants/pharmacology , Caspase 3/metabolism , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Mesangial Cells/metabolism , Mesangial Cells/pathology , Phosphorylation , Poly(ADP-ribose) Polymerases/metabolism , Rats , Signal Transduction/drug effects , Time Factors
6.
Eur Rev Med Pharmacol Sci ; 18(7): 949-58, 2014.
Article in English | MEDLINE | ID: mdl-24763872

ABSTRACT

OBJECTIVES: AMP-activated protein kinase (AMPK) is suggested to exert cytoprotective and anti-inflammatory effects in endothelial cells, but the precise mechanisms are not fully understood. It has been reported that pharmacological activation of AMPK induces endothelial heme oxygenase-1 (HO-1) expression. ß-Lapachone (BL), a well-known substrate of NAD(P)H: quinone oxidoreductase (NQO1), stimulates AMPK activation via NQO1 activation. Here we examined whether AMPK activation by BL would be linked to HO-1 expression in ECV304 endothelial cells and whether HO-1 expression could mediate the cytoprotective effect of BL. MATERIALS AND METHODS: Endothelial cells were pre-incubated for 6 h with BL or 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) in the absence or presence of dicoumarol (DC), compound C (CC), or tin protoporphyrin-IX (SnPP), and then challenged with tumor necrosis factor-α (TNF-α) for 24 h. Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. AMPK phosphorylation and HO-1 expression were detected by Western blot analysis. RESULTS: At non-cytotoxic concentrations, BL induced AMPK phosphorylation and HO-1 expression. AICAR, an AMPK activator, also induced HO-1 expression. In contrast, CC, an inhibitor of AMPK activation, and DC, an inhibitor of NQO1, prevented the increase in BL-induced HO-1 expression. Pretreatment with BL or AICAR reduced TNF-α-induced endothelial cell death. Cytoprotection by BL was almost completely abolished by CC and DC and partly by SnPP, a competitive inhibitor of HO-1. CONCLUSIONS: Our results suggest that BL induces cytoprotective HO-1 expression in endothelial cells via AMPK activation, providing one of possible mechanisms by which BL can exert beneficial effects.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Endothelial Cells/drug effects , Heme Oxygenase-1/metabolism , Naphthoquinones/pharmacology , Protective Agents/pharmacology , Cell Line , Cell Survival/drug effects , Cytoprotection , Endothelial Cells/metabolism , Humans , NAD(P)H Dehydrogenase (Quinone)/metabolism , Tumor Necrosis Factor-alpha/toxicity
7.
J Periodontal Res ; 45(2): 177-83, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20470258

ABSTRACT

BACKGROUND AND OBJECTIVE: Although heme oxygenase-1 (HO-1) plays a key role in inflammation, its anti-inflammatory effects and mechanism of action in periodontitis are still unknown. This study aimed to identify the effects of HO-1 on the proinflammatory mediators activated by nicotine and lipopolysaccharide (LPS) stimulation in human periodontal ligament (PDL) cells. MATERIAL AND METHODS: The production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) was evaluated using Griess reagent and an enzyme immunoassay, respectively. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and HO-1 proteins was evaluated by Western blot analysis. RESULTS: Lipopolysaccharide and nicotine synergistically induced the production of NO and PGE(2) and increased the protein expression of iNOS, COX-2 and HO-1. Treatment with an HO-1 inhibitor and HO-1 small interfering RNAs blocked the LPS- and nicotine-stimulated NO and PGE(2) release as well as the expression of iNOS and COX-2. CONCLUSION: Our data suggest that the nicotine- and LPS-induced inflammatory effects on PDL cells may act through a novel mechanism involving the action of HO-1. Thus, HO-1 may provide a potential therapeutic target for the treatment of periodontal disease associated with smoking and dental plaque.


Subject(s)
Cyclooxygenase 2/drug effects , Heme Oxygenase-1/pharmacology , Lipopolysaccharides/pharmacology , Nicotine/pharmacology , Nitric Oxide Synthase Type II/drug effects , Periodontal Ligament/drug effects , Androstadienes/pharmacology , Anthracenes/pharmacology , Cell Line , Cyclooxygenase 2 Inhibitors/pharmacology , Dinoprostone/analysis , Dinoprostone/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/genetics , Humans , Inflammation Mediators/analysis , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Metalloporphyrins/pharmacology , NF-kappa B/drug effects , Nitric Oxide/analysis , Nitric Oxide/antagonists & inhibitors , Nitric Oxide Synthase Type II/antagonists & inhibitors , Periodontal Ligament/cytology , Periodontal Ligament/enzymology , Phosphoinositide-3 Kinase Inhibitors , Protoporphyrins/pharmacology , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , Transfection , Wortmannin
8.
Inflamm Res ; 56(12): 520-6, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18210237

ABSTRACT

OBJECTIVES: Heme oxygenase (HO)-1 expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation has an ability to inhibit tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. Costunolide has been reported to inhibit IL-1 production, but whether other cytokines could be inhibited remains to be confirmed. We investigated the effects of costunolide and its components (alpha-methylene-gamma-butyrolactone; CH2-BL, alpha-methyl-gamma-butyrolactone; CH3-BL, and gamma-butyrolactone; BL) on HO-1 expression as well as TNF-alpha and IL-6 production in RAW264.7 macrophages. METHODS: HO-1 expression and Nrf2 nuclear accumulation were analyzed by Western blot analysis. The production of TNF-alpha and IL-6 in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) was assayed by ELISA. RESULTS: Costunolide and CH2-BL induced HO-1 expression and Nrf2 nuclear accumulation, whereas CH3-BL and BL did not. Pre-incubation with costunolide inhibited LPS-induced production of TNF-alpha and IL-6. The inhibitory effects of costunolide on TNF-alpha and IL-6 production were abrogated by tin protoporphyrin, an HO inhibitor. CONCLUSIONS: Costunolide is an effective HO-1 inducer capable of inhibiting macrophage-derived pro-inflammatory cytokines. CH2-BL moiety of costunolide is essential for Nrf2 activation leading to HO-1 expression.


Subject(s)
Heme Oxygenase-1/biosynthesis , Interleukin-6/antagonists & inhibitors , Macrophages/drug effects , Sesquiterpenes/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Active Transport, Cell Nucleus , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line , Cell Nucleus/metabolism , Enzyme Induction , Interleukin-6/biosynthesis , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mice , NF-E2-Related Factor 2/metabolism , Plant Extracts/pharmacology , Protoporphyrins/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis
9.
J Dent Res ; 85(6): 515-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16723647

ABSTRACT

UNLABELLED: Cyclosporine A (CsA) is a widely used immunosuppressant but with significant side-effects, such as gingival overgrowth. This study investigates how CsA induces gingival proliferation and shows the effects of the CsA-associated signaling messengers, IL-6 and TGF-beta1, on gingival proliferation. CsA increased both IL-6 and TGF-beta1 levels. In addition to CsA, an IL-6 or TGF-beta1 treatment also induced gingival fibroblast proliferation. Inhibiting the cytokine resulted in the suppression of CsA-induced proliferation. MAPKs and PI3K are known to be involved in cell proliferation. Therefore, the effect of CsA on the kinase activities was examined. The results showed that both p38 MAPK and PI3K are essential for gingival fibroblast proliferation. TGF-beta1 and IL-6 and their associated signaling transduction may be novel bona fide molecular targets for the prevention of gingival overgrowth in CsA-treated patients. ( ABBREVIATIONS: MAPK, mitogen-activated protein kinase; P13K, phosphatidylinositol 3-kinase.)


Subject(s)
Cyclosporine/pharmacology , Gingiva/drug effects , Gingival Overgrowth/chemically induced , Immunosuppressive Agents/pharmacology , Blotting, Northern , Cell Count , Cell Proliferation/drug effects , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/drug effects , Fibroblasts/drug effects , Gingiva/cytology , Humans , Immunoblotting , Immunoprecipitation , Interleukin-6/pharmacology , MAP Kinase Kinase 4/drug effects , Phosphatidylinositol 3-Kinases/drug effects , Signal Transduction/drug effects , Time Factors , Transforming Growth Factor beta/drug effects , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1 , p38 Mitogen-Activated Protein Kinases/drug effects
10.
Clin Chim Acta ; 365(1-2): 270-8, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16242122

ABSTRACT

BACKGROUND: Carbon monoxide (CO) and nitric oxide (NO) each have unique roles for various inflammatory states, including inflammatory bone resorption. Although it is known that NO can induce the expression of the cytoprotective enzyme HO-1, there is no information as to whether the protective effect of CO requires NO production or whether CO must induce the expression of HO-1 to exert its functional effects. METHODS: Murine osteoblast cells, MC3T3E1 osteoblasts, were cultured for CO and NO-associated HO-1 experiments and were transfected with pcDNA 3, pcDNA 3-HO-1, control siRNA or HO-1 siRNA using Nucleofector. For cell death measurement, MTT and annexin V assays were used. We performed Western blotting to check the expressions of HO-1 and iNOs and measured the HO-1 enzyme activity. We also measured the amounts of nitrite and nitrate using Griess reagents. RESULTS: The increased expression of HO-1 is required for the protective effect of NO and a single treatment of CO can increase the expression of HO-1, and this is also important for the protective effect of CO in MC3T3E1 osteoblasts. CO as well as NO attenuates the TNF-alpha-induced apoptosis in osteoblasts. The anti-apoptotic effect of CO or NO is not mediated by cGMP, and CO has no effect on the release of NO. The inhibition of HO-1 with using the HO-1 inhibitor ZnPP or HO-1 siRNA resulted in a striking increase of apoptosis in the CO/TNF-alpha-treated cells. Furthermore, HO-1 overexpression showed resistance against the TNF-alpha-induced cytotoxicity in the MC3T3E1 osteoblasts. CONCLUSIONS: There is a need for HO-1 expression to mediate the protection provided by exogenous CO or NO in osteoblasts.


Subject(s)
Apoptosis/physiology , Carbon Monoxide/physiology , Heme Oxygenase (Decyclizing)/metabolism , Nitric Oxide/physiology , Osteoblasts/cytology , Tumor Necrosis Factor-alpha/physiology , 3T3 Cells , Animals , Blotting, Western , Mice , Osteoblasts/enzymology
11.
Immunopharmacol Immunotoxicol ; 27(4): 631-46, 2005.
Article in English | MEDLINE | ID: mdl-16435581

ABSTRACT

The induction of interleukin-6 (IL-6) using a proinflammatory cytokine (IL-1beta) was studied in human gingival fibroblasts (HGFs) in relation to p38 MAPK and NF-kappaB transcription factor. When added to HGFs, IL-1beta had a stimulatory effect on the production of IL-6, and this effect was significantly reduced by SB203580, a specific p38 MAPK inhibitor. In addition, the stimulation of IL-6 release also was reduced by the addition of pyrrolidine dithiocarbamate or NF-kappaB SN50, which has been reported as potent NF-kappaB inhibitor. Both the NF-kappaB inhibitors in the presence of SB203580 had more inhibitory effect on IL-6 release. IL-13 stimulated NF-kappaB binding affinity as well as p38 MAP kinase activation, leading to the release of IL-6. However, a specific inhibitor of p38 MAPK, SB203580, had no effect on the NF-kappaB activation, and both the NF-kappaB inhibitors failed to reduce the p38 MAPK activation in the IL-1beta-stimulated HGFs. These results strongly suggest that both p38 MAPK and NF-kappaB are required in IL-1beta-induced IL-6 synthesis and that these two IL-1beta-activated pathways can be primarily dissociated.


Subject(s)
Fibroblasts/metabolism , Interleukin-6/metabolism , NF-kappa B/metabolism , RNA, Messenger/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Gingiva/cytology , Gingiva/drug effects , Gingiva/metabolism , Humans , Imidazoles/pharmacology , Interleukin-1/pharmacology , Interleukin-6/genetics , NF-kappa B/antagonists & inhibitors , Peptides/pharmacology , Phosphorylation , Pyridines/pharmacology , Pyrrolidines/pharmacology , Signal Transduction/drug effects , Thiocarbamates/pharmacology , Time Factors , Transcription, Genetic/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
12.
Immunopharmacol Immunotoxicol ; 26(3): 343-53, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15518169

ABSTRACT

We studied the effect of mokko lactone (ML) isolated from the roots of Saussurea lappa (Compositae), a plant that is used for medicinal purposes in Korea, on the induction of apoptosis in human leukemia HL-60 cells. ML was cytotoxic to HL-60 cells, and this cytotoxic effect of ML appears to be attributable to its induction of apoptotic cell death, as ML induced nuclear morphologic changes and internucleosomal DNA fragmentation and increased the proportion of Annexin V-positive cells and the activity of caspase-3. Further studies revealed that the induction of apoptosis by ML was associated with the loss of mitochondrial membrane potential. Collectively, our results suggest that apoptosis induced by ML in HL-60 cells was executed by a collapse of mitochondrial membrane potential followed by the activation of caspase-3. This is the first report on the mechanism of apoptosis-inducing effect of ML.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , HL-60 Cells/drug effects , Intracellular Membranes/drug effects , Lactones/pharmacology , Mitochondria/drug effects , Saussurea , Sesquiterpenes/pharmacology , 4-Butyrolactone/isolation & purification , Caspase 3 , Caspases/analysis , Caspases/metabolism , DNA Fragmentation , Humans , Intracellular Membranes/pathology , Korea , Lactones/isolation & purification , Membrane Potentials/drug effects , Mitochondria/pathology , Plant Roots/chemistry , Saussurea/chemistry , Sesquiterpenes/isolation & purification
13.
Immunopharmacol Immunotoxicol ; 26(2): 163-75, 2004 May.
Article in English | MEDLINE | ID: mdl-15209353

ABSTRACT

Sesquiterpene lactones have raised considerable interest because of their ability to block the activation of nuclear transcription factor-kappaB (NF-kappaB). NF-kappaB plays an important role in the resistance of cancer cells to the induction of apoptosis by anticancer drugs and tumor necrosis factor-alpha (TNF-alpha). Pharmacological inhibition of NF-kappaB offers the promise of enhancing the efficacy of anticancer therapies. Here, we demonstrate that dehydrocostus lactone (DL), the major sesquiterpene lactone isolated from the roots of Saussurea lappa, inhibits NF-kappaB activation by preventing TNF-alpha-induced degradation and phosphorylation of its inhibitory protein I-kappaB alpha in human leukemia HL-60 cells and that DL renders HL-60 cells susceptible to TNF-alpha-induced apoptosis by enhancing caspase-8 and caspase-3 activities.


Subject(s)
Apoptosis/drug effects , Lactones/administration & dosage , Sesquiterpenes/administration & dosage , Tumor Necrosis Factor-alpha/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/isolation & purification , Caspase 3 , Caspase 8 , Caspases/metabolism , Drug Synergism , HL-60 Cells , Humans , Lactones/isolation & purification , NF-kappa B/metabolism , Neoplasm Proteins/biosynthesis , Phytotherapy , Saussurea/chemistry , Sesquiterpenes/isolation & purification
14.
Int Immunopharmacol ; 4(3): 377-86, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15037215

ABSTRACT

We investigated the effects of the gallotannin penta-O-galloyl-beta-d-glucose (PGG) on interleukin (IL)-8 gene expression and nuclear factor (NF)-kappaB activation. PGG inhibited IL-8 production and gene expression in human monocytic U937 cells stimulated with phorbol myristate acetate (PMA), as measured by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction analysis, respectively. PGG also inhibited PMA-mediated NF-kappaB activation, as measured by electromobility shift assay. Furthermore, PGG prevented PMA-mediated degradation of the NF-kappaB inhibitory protein I-kappaBalpha, as measured by Western blot analysis. PGG also inhibited both IL-8 production and NF-kappaB activation in the U937 cells stimulated with tumor necrosis factor-alpha. These results suggest that PGG, a major constituent of the root cortex of Paeonia suffruticosa ANDREWS, can inhibit IL-8 gene expression by a mechanism involving its inhibition of NF-kappaB activation, which is dependent on I-kappaBalpha degradation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Hydrolyzable Tannins/pharmacology , Interleukin-8/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Tetradecanoylphorbol Acetate/pharmacology , Active Transport, Cell Nucleus , Blotting, Western , Electrophoretic Mobility Shift Assay , Enzyme-Linked Immunosorbent Assay , Gene Expression Regulation , Humans , I-kappa B Proteins/metabolism , Interleukin-8/biosynthesis , Interleukin-8/genetics , Protein Transport , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , U937 Cells
15.
Cancer Lett ; 205(1): 23-9, 2004 Mar 08.
Article in English | MEDLINE | ID: mdl-15036657

ABSTRACT

Ginsenosides from Panax ginseng are metabolized by human intestinal bacteria after oral administration of ginseng extract. 20(S)-Protopanaxatriol (PPT) is one of the major metabolites of ginsenosides. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important enzymes that mediate inflammatory processes. Improper up-regulation of iNOS and/or COX-2 has been associated with the pathogenesis of inflammatory diseases and certain types of human cancers. Here, we investigated whether PPT could modulate iNOS and COX-2 expressions in RAW 264.7 macrophages stimulated with the endotoxin lipopolysaccharide (LPS). We found that PPT blocked the increase in LPS-induced iNOS and COX-2 expressions through inactivation of nuclear factor-kappaB by preventing I-kappaBalpha phosphorylation and degradation. Thus, it may be possible to develop PPT as a useful agent for chemoprevention of cancer or inflammatory diseases.


Subject(s)
Isoenzymes/drug effects , Macrophages/drug effects , NF-kappa B/drug effects , Nitric Oxide Synthase/drug effects , Prostaglandin-Endoperoxide Synthases/drug effects , Sapogenins/pharmacology , Triterpenes/pharmacology , Animals , Blotting, Western , Cells, Cultured , Cyclooxygenase 2 , Electrophoretic Mobility Shift Assay , Ginsenosides/metabolism , Isoenzymes/biosynthesis , Lipopolysaccharides/pharmacology , Macrophage Activation , Macrophages/metabolism , Mice , NF-kappa B/metabolism , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase Type II , Prostaglandin-Endoperoxide Synthases/biosynthesis
16.
Immunopharmacol Immunotoxicol ; 25(4): 585-94, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14686800

ABSTRACT

The protective effects of baicalin (BA), a major flavone from Scutellaria radix, on acetaminophen (AP)-induced hepatotoxicity and the possible mechanism(s) of its protective action were investigated in mice. Treatment with BA (300 mg/kg, p.o.) 0.5 h after AP administration significantly prevented an increase in plasma alanine aminotransferase and aspartate aminotransferase activities and AP-induced hepatic necrosis, and also reduced AP-induced mortality from 43% to 0%. In addition, oral treatment with BA significantly prevented AP-induced depletion of glutathione (GSH) contents. However, BA treatment, by itself, did not affect hepatic GSH contents. The effect of BA on the cytochrome P450 2E1 (CYP2E1), the major isozyme involved in AP bioactivation, was investigated. Oral treatment of mice with BA resulted in a significant decrease in AP-induced CYP2E1 activity together with its inhibition of AP-induced CYP2EI expression. These results show that the hepatoprotective effects of BA against AP overdose may be due to its ability to block the bioactivation of AP by inhibiting CYP2E1 expression.


Subject(s)
Acetaminophen/toxicity , Flavonoids/pharmacology , Liver/drug effects , Liver/injuries , Phytotherapy , Scutellaria baicalensis , Acetaminophen/pharmacokinetics , Administration, Oral , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Cytochrome P-450 CYP2E1/metabolism , Flavonoids/administration & dosage , Flavonoids/isolation & purification , Glutathione/metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred BALB C , Scutellaria baicalensis/chemistry
17.
J Ethnopharmacol ; 88(2-3): 287-91, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12963157

ABSTRACT

In order to validate the use of the stem bark of Catalpa ovata G. Don. (Bignoniaceae) as an anti-inflammatory drug in the traditional Korean medicine, we have investigated the effects of the methanol extract of this folk medicine on the productions of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) on RAW 264.7 macrophages activated with the endotoxin lipopolysaccharide. The extract inhibited the productions of TNF-alpha and NO with significant decreases in mRNA levels of TNF-alpha and inducible NO synthase, suggesting that the stem bark of Catalpa ovata may have therapeutic potential in the control of inflammatory disorders.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bignoniaceae/chemistry , Macrophages/drug effects , Nitric Oxide/biosynthesis , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Blotting, Western , Cell Line , Cell Survival/drug effects , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mice , Plant Bark/chemistry , Plant Extracts/pharmacology , RNA, Messenger/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction
18.
Immunopharmacol Immunotoxicol ; 25(1): 41-52, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12675198

ABSTRACT

Experimental allergic encephalomyelitis (EAE) is an autoimmune CD4+ T cell-mediated disease of the central nervous system (CNS). Nitric oxide (NO) plays an important role in preventing the development of EAE. Molsidomine (Mol) is a drug used for the treatment of coronary artery disease. Its therapeutic effects are the consequences of NO formation. In this study, we investigated the effects of Mol on EAE development in myelin basic protein (MBP)-immunized Lewis rats. All rats immunized with MBP developed typical clinical signs of acute EAE. In the EAE rats receiving Mol, the severity of clinical signs and the infiltration of inflammatory cells in CNS were clearly reduced. Furthermore, Mol administration significantly reduced the production of interferon-gamma, a Th1 inflammatory cytokine, but increased the production of interleukin-10, a Th2 anti-inflammatory cytokine. Our findings suggest that the administration of the exogenous NO donor Mol is of considerable benefit in limiting the development of EAE and other Th1 cell-mediated inflammatory diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/prevention & control , Molsidomine/therapeutic use , Nitric Oxide Donors/therapeutic use , Animals , Cytokines/drug effects , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/pathology , Immunohistochemistry , Interferon-gamma/metabolism , Interleukin-10/metabolism , Male , Molsidomine/pharmacology , Myelin Basic Protein , Myelitis/pathology , Myelitis/physiopathology , Nitric Oxide Donors/pharmacology , Rats , Rats, Inbred Lew
19.
Toxicol In Vitro ; 17(1): 49-57, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12537962

ABSTRACT

Recently we have reported that the trichothecene mycotoxin 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol (AETD) from the fruiting bodies of Isaria japonica Yasuda is a potent inducer of apoptosis in human promyelocytic HL-60 cells. The present study aims to characterize the molecular events leading to AETD-induced apoptosis in HL-60 cells. The percentage of apoptotic cells (annexin-V-positive cell population) increased dose- and time-dependently after AETD exposure. Apoptosis of HL-60 cells by AETD was associated with the formation of intracellular reactive oxygen species (ROS), the depletion of intracellular glutathione (GSH) and the activation of caspase-3. Pretreating the cells with the antioxidant N-acetyl-L-cystein (NAC) and the caspase-3 inhibitor Z-DEVD-fmk abrogated AETD-induced apoptosis and caspase-3 activation. NAC blocked intracellular ROS formation and GSH depletion, but Z-DEVD-fmk did not. These results indicate that AETD induces apoptosis in HL-60 cells by causing intracellular ROS formation and GSH depletion followed by the downstream event of caspase-3 activation.


Subject(s)
Apoptosis/drug effects , Ascomycota/chemistry , Reactive Oxygen Species/adverse effects , Trichothecenes/pharmacology , Caspase 3 , Caspases/pharmacology , Dose-Response Relationship, Drug , Glutathione/metabolism , HL-60 Cells , Humans
20.
Immunopharmacol Immunotoxicol ; 25(3): 295-304, 2003 Aug.
Article in English | MEDLINE | ID: mdl-19180794

ABSTRACT

The amyloid beta-peptide (Abeta)-induced oxidative stress is a well-established pathway of neuronal cell death in Alzheimer's disease (AD). Salidroside, one of the major compounds from the roots of Rhodiola species (Crassulaceae), was investigated in vitro for its cytoprotection against Abeta-induced toxicity on rat neuronal PCl2 cells. Salidroside significantly reduced Abeta-induced cytotoxicity in a dose-dependent manner. Salidroside also reduced Abeta-mediated intracellular accumulation of reactive oxygen species and malondialdehyde (MDA), a product of lipid peroxides, by preventing Abeta-induced decline of antioxidant enzyme activities. These results suggest that salidroside protects neuronal PC12 cells from Abeta-induced cytotoxicity via its antioxidant pathway.


Subject(s)
Amyloid beta-Peptides/metabolism , Antioxidants/pharmacology , Cytoprotection , Glucosides/pharmacology , Neurons/drug effects , Oxidative Stress/drug effects , Phenols/pharmacology , Rhodiola , Animals , Cell Death , Cell Survival/drug effects , Dose-Response Relationship, Drug , Glucosides/isolation & purification , Lipid Peroxidation/drug effects , Malondialdehyde/metabolism , Neurons/metabolism , Neurons/pathology , PC12 Cells , Phenols/isolation & purification , Plant Roots , Rats , Reactive Oxygen Species/metabolism , Rhodiola/chemistry
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