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PubMed2003

Cytosolic and mitochondrial ROS in staurosporine-induced retinal cell apoptosis.

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.

Adenine↗

PubMed2005

Mitochondrial H(+) leak and ROS generation: an odd couple.

The single-electron chemistry of mitochondrial oxidative phosphorylation (ox-phos) by default generates reactive oxygen species (ROS). These ROS have roles in both physiologic cell signaling and numerous pathologic situations. One factor that has the potential to regulate ROS generation is the mild uncoupling of ox-phos, i.e., proton (H(+)) leak across the mitochondrial inner membrane. Proton leak has been shown to decrease ROS generation, whereas ROS have been shown to induce H(+) leak, and this suggests the existence of a feedback loop between ROS and H(+) leak. Interestingly, although H(+) leak is detrimental to ATP synthesis, it has been shown to be cytoprotective in several models of ischemic injury. Herein the molecular basis of both ROS generation and H(+) leak will be reviewed and the consequences of their interaction for mitochondrial function discussed.

Animals↗

PubMed2005

Production of reactive oxygen species (ROS) by devil stinger (Inimicus japonicus) during embryogenesis.

In aqua-cultural industry, the seed production of devil stinger, a valuable fish in Japan, has not succeeded yet due to the cryptogenic mass mortality. We found that survival rate of the larvae of devil stinger increased by the addition of green tea extract rich in catechin into rearing tank. Generation of reactive oxygen species (ROS) was detected in the embryo of devil stinger by chemiluminescence analysis under the normal growth conditions without addition of specific stimulants. Even in the unfertilized egg, certain level of ROS was detected. ROS were continuously detected during the development from fertilized egg to larva and tended to increase gradually. Observation of embryos and post-hatching larvae with hypersensitive photon-counting microscopy indicated that ROS were produced on the surface of embryo and the head region of larva especially peripheries of eyes. When the embryo proteins were analyzed by immunoblotting using antibody against the human neutrophil cytochrome b558 large subunit (gp91 phox), a main band of approximately 91 kDa was detected, suggesting the presence of NADPH oxidase-like ROS generating system in the embryo of devil stinger. After treatment with streptomycin and penicillin G for 1 day, the level of ROS production in larvae decreased with increase in the survival rate of larvae. Our results suggest that devil stinger has ROS generation system that is already activated at fairly early stage of development before the maturation of usual immune system.

Animals↗

PubMed2004

Catechins prevents substance P-induced hyperactive bladder in rats via the downregulation of ICAM and ROS.

We previously reported substance P (SP) via neurokinin type 1 receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder connected with neurogenic inflammation [Am. J. Physiol. Renal Physiol. 284 (2003) F840]. Increased intercellular adhesion molecule expression and subsequent leukocyte adhesion in the inflamed bladder contribute to SP-induced oxidative injury. Here we investigate the effect of green tea extract (catechins) on SP-induced bladder hyperactivity. We evaluated isovolumetric cystometrogram, adhesion molecular expression, and ROS activity in anesthetized rat bladder with SP stimulation. Our results showed that SP increased the amount of leukocyte ROS production in vitro in a dose-dependent manner and the enhanced ROS can be inhibited by catechins treatment. Exogenous SP increased ROS in vivo in the bladder via increased intercellular adhesion molecule expression and subsequent leukocyte adhesion, a primary source of ROS in the inflamed bladder. Two weeks of catechins pretreatment reduced SP-induced bladder intercellular adhesion molecule expression and ROS amount and ameliorated the hyperactive bladder response. These results indicate that catechins pretreatment can ameliorate SP-induced neurogenic inflammation via the action of antioxidant, anti-adhesion, and anti-inflammatory activity.

Animals↗

PubMed2006

ROS scavenging effects of organic extract of diesel exhaust particles on human neutrophil granulocytes and rat alveolar macrophages.

Diesel exhaust particles are major constituents of ambient air pollution, and are associated with respiratory and cardiovascular diseases and lung cancer. The organic part of the particles is heterogenic and complex, and seems to be responsible for many of the adverse effects. Increased formation of ROS is often connected to the adverse effects. We have therefore investigated the effect of an organic extract of diesel exhaust particles on the reactive oxygen species (ROS) status in human neutrophil granulocytes and rat alveolar macrophages in vitro. ROS formation were studied by three different assays namely the use of DCFH-DA, lucigenin and luminol. The organic extract increased ROS assayed with DCFH-DA, but it decreased the amount of ROS in cells stimulated by PMA in all three assays. The identities of the ROS affected were further studied in cell free systems. The cell free studies confirmed that the extract had scavenging effects against superoxide, hypochlorite and to a smaller extent against peroxynitrite, but not against the hydroxyl radical and nitric oxide. ROS take part in the intracellular signalling pathways as well as in the defence against invading microorganisms, and the possible effects of interference of the redox status in the cells are discussed.

Acridines↗

PubMed2003

IL-1alpha-induced COX-2 expression in human intestinal myofibroblasts is dependent on a PKCzeta-ROS pathway.

BACKGROUND & AIMS: Intestinal myofibroblasts (IMFs) express cyclooxygenase 2 (COX-2) early on in polyp progression and respond to pro-inflammatory cytokines. Interleukin (IL)-1alpha induces COX-2 expression in IMF via mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and nuclear factor kappa B (NF-kappaB)-dependent pathways. Because NF-kappaB activity can be mediated by PKC activation and reactive oxygen species (ROS) generation, we examined the relationship of these pathways to IL-1alpha-induced COX-2 expression. METHODS: The effects of specific PKC inhibitors and antioxidants on PKC activation, ROS generation, and COX-2 expression were studied. RESULTS: Immunoprecipitation/kinase (IPK) analysis showed that IL-1alpha increased PKC alpha, delta, and zeta activity 4.5-, 3.1-, and 2.6-fold, respectively, within 5 minutes. Single-cell fluorescence microscopy of 2',7'-dichlorofluorescin diacetate (DCF)-loaded cells showed that IL-1alpha increased ROS levels 2-fold within 15 minutes and this increase was inhibited by 10 micromol/L bisindolylymaleimide I (BIS), a pan-specific PKC inhibitor that also inhibits COX-2 expression. Chelerythrine chloride (CC) (0.5 micromol/L) inhibited classic and novel PKC activity, but not PKCzeta, and enhanced IL-1alpha-mediated ROS generation 4.0-fold and COX-2 expression 1.8-fold. The use of a PKCzeta pseudosubstrate prevented IL-1 from increasing ROS greater than control levels and abolished IL-1alpha-induced COX-2 expression. Small inhibitory RNA (siRNA) for PKCzeta confirmed its role in COX-2 expression. Antioxidants inhibited ROS generation and diminished IL-1alpha-induced COX-2 expression by 80%, without affecting PKC activation. Neither the PKC inhibitors nor the antioxidants prevented NF-kappaB-mediated transcription as determined by reporter gene analysis. CONCLUSIONS: PKCzeta and threshold ROS generation are critical for IL-1alpha-induced COX-2 expression and act concomitantly with NF-kappaB translocation in IMF.

Antioxidants↗

PubMed2001

Involvement of NADH/NADPH oxidase in human platelet ROS production.

Platelets play an important role in atherosclerotic and thromboembolic vascular diseases. It has been reported that reactive oxygen species (ROS) could modify platelet function, and platelets themselves have the ability to produce ROS. However, the enzymatic sources of ROS in platelets have not been fully determined. The NADH/NADPH oxidase system was originally identified as the major source of ROS in phagocytes. Recently, it has become evident that this oxidase is functionally expressed not only in phagocytes but also in various cell types. The present study was undertaken to test the hypothesis that NADH/NADPH oxidase might be expressed in human platelets. Lucigenin-enhanced chemiluminescence (L-CL) and electron spin resonance (ESR) method demonstrated that human platelets obtained from healthy volunteers released ROS, and the released ROS were increased by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) or calcium ionophore. Homogenates of human platelets, as well as MEG01 cells, megakaryocytic cell line, had the enzymatic activity to produce superoxide in NADH/NADPH-dependent manners. This enzymatic activity was suppressed by diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase. Western blot analysis demonstrated that platelets and MEG01 cells expressed p22(phox) and p67(phox) proteins, components of NADH/NADPH oxidase. Thus, human platelets have the enzymatic activity of p22(phox)-based NADH/NADPH oxidase, and this oxidase is likely one of the important sources of ROS in platelets.

Blood Platelets↗

PubMed2003

Both calcium and ROS as common signals mediate Na(2)SeO(3)-induced apoptosis in SW480 human colonic carcinoma cells.

Recent studies have shown that reactive oxygen species (ROS) play a crucial role in Se-induced cell apoptosis. A number of studies have demonstrated that perturbed cellular calcium homeostasis has been implicated in apoptosis. The main objective of this study was to evaluate the role of Ca(2+) in Na(2)SeO(3)-induced apoptosis and the relationship between Ca(2+) and ROS in human colonic carcinoma cells SW480. When SW480 cells were exposed to 25-100 microM Na(2)SeO(3), both cell apoptosis and growth inhibition were observed by flow cytometric analysis and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Na(2)SeO(3) was able to induce increase of [Ca(2+)](i) and ROS production and disrupt mitochondrial membrane potential (Delta Psi m) in SW480 cells monitored by using a confocal laser scanning microscope. Ca(2+) channel inhibitor CoCl(2) and an intracellular Ca(2+) chelator o-phtalaldehyde, 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA) completely inhibited [Ca(2+)](i) increase, but catalase had no effect on Na(2)SeO(3)-induced increase of [Ca(2+)](i). BAPTA-AM, CoCl(2), and mitochondrial Ca(2+) uptake inhibitor ruthenium red blocked Delta Psi m dissipation. The increase of ROS was also suppressed by CoCl(2), BAPTA, ruthenium red, N-acetylcysteine and catalase, respectively. The mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) completely inhibited Na(2)SeO(3)-induced ROS increase. This showed that ROS increase is due to mitochondrial Ca(2+) overload. The Na(2)SeO(3)-induced apoptosis of SW480 cells was also inhibited by CoCl(2), BAPTA, ruthenium red, N-acetylcysteine, and catalase, respectively. The results mentioned above imply that both calcium and Ca(2+)-dependent ROS as a signal molecule mediate apoptosis induced by Na(2)SeO(3) in SW480 cells.

Acetylcysteine↗

PubMed2002

Mechanism of silica-induced ROS generation in Rat2 fibroblast cells.

Reactive oxygen species (ROS) play an important role in cell signaling pathway. Previously, we found that silica induced immediate ROS generation and sequential cellular responses such as kinase activation in Rat2 cells as well as an increase of intracellular calcium concentration in A549 cells. However, the detailed mechanism underlying the immediate ROS generation induced by silica in fibroblast cells remains to be elucidated. Therefore, in the present study, we investigated the mechanism of ROS generation by silica within Rat2 fibroblast cells by examining the effects of a diverse group of inhibitors for the enzymes related with signal transduction events. Inhibitors for protein tyrosine kinase (PTK), phospholipase C (PLC), protein kinase C (PKC) and calmodulin (CaM) kinase II effectively suppressed ROS generation in silica-stimulated Rat2 cells, whereas those for protein kinase A and phospholipase A(2) did not. Diphenyleneiodonium chloride (DPI), an inhibitor for NADPH oxidase was also found to be effective in inhibiting silica-induced ROS generation. These results suggest that PTK, PLC, PKC, CaM kinase II, and NADPH oxidase are all involved in signal transduction pathways for ROS generation in silica-stimulated Rat2 cells.

Animals↗

PubMedDate not supplied

Comparative effects of cadmium, copper, paraquat and benzo[a]pyrene on the actin cytoskeleton and production of reactive oxygen species (ROS) in mussel haemocytes.

The immune defence of mussels is comprised of cell-mediated and humoral mechanisms, in which haemocytes or blood cells play a key role. Environmental pollutants such as metallic and organic xenobiotics exert immunotoxical effects on aquatic organisms. Some of these xenobiotics are known to give rise to highly reactive oxygen species (ROS), thereby leading to oxidative damage to tissue macromolecules including DNA, proteins and lipids. Previously we have detected enhancement of ROS production together with severe alterations in the actin cytoskeleton after exposure of mussel haemocytes to the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (b[a]p). In a similar way, cadmium is also known to cause disruption of the actin cytoskeleton in mussel haemocytes, however it is not known whether this effect occurs by direct action or through ROS production. The aim of the present study was to decipher whether cytoskeletal alterations caused by Cd in mussel haemocytes are linked to increased ROS production. ROS-producing model compounds copper (Cu), paraquat and b[a]p were used in parallel experiments for comparative purposes. In all contaminant exposure experiments actin cytoskeleton appeared damaged. On the other hand, ROS production was increased in paraquat and b[a]p exposure experiments but decreased in haemocytes exposed to Cu while no significant effects were detected in Cd exposure experiments. In conclusion, it appears that deleterious effects of Cu and Cd on the integrity of the actin cytoskeleton of haemocytes are not directly linked to ROS production, at least at the exposure conditions used in the present study.

Actins↗

PubMed2003

Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis.

Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in a variety of cancer cells, including those of colon, prostate, breast, and leukemia. We examined the effects of sodium salicylate (NaSal) on reactive oxygen species (ROS) production and the association of these effects with apoptotic tumor cell death. We demonstrate that NaSal mediates ROS production followed by a decrease in mitochondrial membrane potential (deltapsi(m)), release of cytochrome c, and activation of caspase-9 and caspase-3. However, expression of Bcl-2 or Bcl-x(L) prevents ROS production and subsequent loss of deltapsi(m), thereby inhibiting apoptotic cell death. The presence of ROS scavengers and an inhibitor of NADPH oxidase or expression of a dominant negative form of Rac1 blocks ROS production, deltapsi(m) collapse, and the subsequent activation of caspases. These observations indicate that NaSal mediates ROS production critical in the triggering of apoptotic tumor cell death through a Rac1-NADPH oxidase-dependent pathway. Our data collectively imply that NaSal-induced ROS are key mediators of deltapsi(m) collapse, which leads to the release of cytochrome c followed by caspase activation, culminating in tumor apoptosis.

Adenocarcinoma↗

PubMed2005

HSP25 inhibits radiation-induced apoptosis through reduction of PKCdelta-mediated ROS production.

Since radiation-induced caspase-dependent apoptosis and ROS generation were partially prevented by HSP25 overexpression, similar to the treatment of control cells with antioxidant agents such as DPI and tiron, questions arise whether radiation-mediated ROS generation contributes to the apoptotic cell death, and also whether HSP25 overexpression can reduce ROS mediated apoptotic cell death. In the present study, radiation-induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential in Jurkat T cells were shown to be inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpressed, effects similar to the treatment of cells with the antioxidants were obtained, indicating that HSP25 suppressed radiation-induced mitochondrial alteration that resulted in apoptosis. Furthermore, activation of p38 MAP kinase by radiation was associated with radiation-induced cell death and ROS production and PKCdelta was an upstream molecule for p38 MAP kinase activation, ROS generation and subsequent caspase-dependent apoptotic events. However, in the HSP25 overexpressed cells, the above-described effects were blocked. In fact, radiation-induced membrane translocation of PKCdelta and tyrosine phosphorylation were inhibited by HSP25. Based on the above data, we suggest that HSP25 downregulates PKCdelta, which is a key molecule for radiation-induced ROS generation and mitochondrial-mediated caspase-dependent apoptotic events.

Apoptosis↗

PubMed2002

Inhibitory effect of terbinafine on reactive oxygen species (ROS) generation by Candida albicans.

Candida albicans, the most important opportunistic fungal pathogen, is able to generate remarkable amounts of reactive oxygen species (ROS). Since ROS are highly cytotoxic, this mechanism may contribute to the pathogenicity of this yeast, including its invasiveness and the inflammatory response of the host. Terbinafine, a synthetic antifungal agent of the allylamine class, inhibits ergosterol biosynthesis at the level of squalene epoxidase. Furthermore, there is evidence that terbinafine at therapeutic concentrations can be considered a free radical scavenger in vitro and could exert an anti-inflammatory activity in vivo. In this study we investigated whether terbinafine affects the generation of ROS by C. albicans. Blastoconidia of the C. albicans strain 3153A were cultured in YEPG-medium and, subsequently, incubated with different doses of terbinafine (1, 10 and 100 microg ml(-1)) for 10 and 60 min, respectively. ROS generation was measured by lucigenin-enhanced chemiluminescence. Formation of ROS was considerably dependent on cell number. Chemiluminescence signals were measured at a concentration > or = 1 x 10(6) cells ml(-1), with a maximum of 1 x 10(8) cells ml(-)1. Already after 10 min of incubation with terbinafine, a dose-dependent significant inhibition of ROS generation was found (P < 0.05), whereas after 60 min this effect was amplified. In conclusion, terbinafine reduced the ability of C. albicans to generate ROS. Besides the known effect on ergosterol biosynthesis, this mechanism may contribute to its antifungal action.

Antifungal Agents↗

PubMed2007

Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications.

In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes and its complications are described. In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all of which are believed to be the main molecular mechanisms of diabetic complications. Glomerular hyperfiltration, one of the characteristics of early diabetic nephropathy, may be caused by mitochondrial ROS through activation of COX-2 gene transcription, followed by PGE2 overproduction. In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppresses the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH2-terminal kinases (JNK), increases serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. These results suggest the importance of mitochondrial ROS in the pathogenesis of diabetes mellitus and its complications through modification of various cellular events in many tissues, including vessels, kidney, pancreatic beta cells, and liver.

AMP-Activated Protein Kinases↗

PubMed2002

Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence.

The cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1/Sdi1) was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence. Reactive oxygen species (ROS), a byproduct of oxidative processes, can also induce an irreversible growth arrest similar to senescence. Here we show that p21 increased intracellular levels of ROS both in normal fibroblasts and in p53-negative cancer cells. N-acetyl-L-cysteine, an ROS inhibitor, rescued p21-induced senescence, showing that ROS elevation is necessary for induction of the permanent growth arrest phenotype. p16(Ink4a), a CDK4- and CDK6-specific inhibitor, failed to increase ROS levels, and cell cycle arrest induced by p16 was reversible following its down-regulation, demonstrating the specificity of this p21 effect. A p21 mutant that lacked the ability to bind proliferating cell nuclear antigen (PCNA) retained the ability to induce both ROS and permanent growth arrest. All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16.

Acetylcysteine↗

PubMed1996

The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis.

The c-ros gene was originally identified in mutant form as an oncogene. The proto-oncogene encodes a tyrosine kinase receptor that is expressed in a small number of epithelial cell types, including those of the epididymis. Targeted mutations of c-ros in the mouse reveal an essential role of the gene in male fertility. Male c-ros -/- animals do not reproduce, whereas the fertility of female animals is not affected. We demonstrate that c-ros is not required in a cell autonomous manner for male germ cell development or function. The gene, therefore, does not affect sperm generation or function in a direct manner. The primary defect in the mutant animals was located in the epididymis, showing that c-ros controls appropriate development of the epithelia, particularly regionalization and terminal differentiation. The epididymal defect does not interfere with production or storage of sperm but, rather, with sperm maturation and the ability of sperm to fertilize in vivo. Interestingly, sperm isolated from c-ros -/- animals can fertilize in vitro. Our results highlight the essential role of the epididymis in male fertility and demonstrate a highly specific function of the c-ros receptor tyrosine kinase during development of distinct epithelial cells.

Animals↗

PubMed2007

Quantification of basal and stimulated ROS levels as predictors of islet potency and function.

We have developed a luminol-based assay using intact islets, which allows for quantification of reactive oxygen species (ROS). In addition, an index capable of characterizing metabolic and mitochondrial integrity prior to transplantation was created based on the capacity of islets to respond to high glucose and rotenone (mitochondrial respiratory chain complex I inhibitor) by production of ROS. To validate this assay, lipid peroxidation and antioxidative defense capacity were evaluated by detection of malondialdehyde (MDA) levels and glutathione peroxidase activity (GPx), respectively. Also, flow cytometric analyses of ROS (dihydroethidine), apoptosis (Annexin V, active caspases), necrosis (Topro3), and mitochondrial membrane potential (JC-1) were done in parallel to correlate with changes in luminol-measured ROS. ATP/ADP ratios were quantified by HPLC and the predictive value of ROS measurement on islet functional potency was correlated with capacity to reverse diabetes in a streptozotocin-induced diabetic NOD.scid mouse model as well as in human transplant recipients. Our data demonstrate that levels of ROS in islets correlate with the percentage of apoptotic cells and their functional potency in vivo. The ROS indices following glucose and rotenone exposure are indicative of metabolic potency and mitochondrial integrity and can be used as surrogate markers to evaluate the quality of islets prior to transplantation.

Animals↗

PubMed2005

Relationship between intracellular ROS production and membrane mobility in curcumin- and tetrahydrocurcumin-treated human gingival fibroblasts and human submandibular gland carcinoma cells.

OBJECTIVE: Curcumin is a well-known chemopreventive agent of oral cancers as well as stomach and intestinal cancers. The relationship between reactive oxygen species (ROS) production and cell membrane mobility was investigated to clarify the pro-oxidant mechanism of curcumin and tetrahydrocurcumin (TH-curcumin). METHODS: The intracellular ROS production and membrane mobility by curcumin or TH-curcumin were measured in human submandibular adenocarcinoma cells (HSGs) and human primary gingival fibroblasts (HGFs). ROS and mobility were measured by 5-(and -6)-carboxy-2',7'-dichlorofluorescein diacetate staining and fluorescence recovery after photo bleaching, respectively. RESULTS: Curcumin produced ROS dose-dependently. ROS appeared in the region surrounding the cell membrane. The membrane mobility coefficient of the curcumin-treated cells was significantly lower than that of control cells. The lowered membrane mobility induced by curcumin was reversed by the addition of glutathione, an antioxidant. In contrast, TH-curcumin did not affect the ROS production or the membrane mobility coefficient. The alternations induced by curcumin treated HSG cells were greater than those by HGF cells. CONCLUSION: The reduction in membrane mobility induced by curcumin was attributed to ROS production. The oxidative effects of curcumin may be related to the structure of the alpha, beta-unsaturated carbonyl moiety as well as the phenolic OH group of this compound.

Adenocarcinoma↗